WO2024046277A1 - Series of nitrogen-containing bridged heterocyclic compounds and preparation method therefor - Google Patents

Series of nitrogen-containing bridged heterocyclic compounds and preparation method therefor Download PDF

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WO2024046277A1
WO2024046277A1 PCT/CN2023/115288 CN2023115288W WO2024046277A1 WO 2024046277 A1 WO2024046277 A1 WO 2024046277A1 CN 2023115288 W CN2023115288 W CN 2023115288W WO 2024046277 A1 WO2024046277 A1 WO 2024046277A1
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alkyl
compound
optionally substituted
present
independently
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PCT/CN2023/115288
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颜小兵
钱文远
陈曙辉
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南京明德新药研发有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a series of nitrogen-containing bridged heterocyclic compounds and their preparation methods, specifically to the compounds represented by formula (I) and their pharmaceutically acceptable salts.
  • the complement system consists of more than 50 proteins that can be precisely regulated. It is an important part of the human body's innate immunity and serves as a bridge between innate immunity and acquired immunity.
  • the complement system is mainly activated through three pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP).
  • C3 convertase and C5 convertase These three activation pathways are centered on the formation of C3 convertase and C5 convertase. They produce corresponding bioactive fragments by cleaving C3 and C5 to further amplify the complement reaction. These fragments modify the target surface and can promote phagocytosis, inflammation, immune regulation, etc. process. Among them, the reaction from contact with the activation starter to the generation of C3 convertase (and cleavage of C3) can be regarded as the front-end reaction of these activation pathways.
  • Complement Factor B acts on the AP pathway. Inhibiting Factor B activity can prevent the activation of the AP pathway without interfering with the CP and LP pathways, and can reduce the risk of infection caused by increased inhibition of the complement system.
  • Novartis' factor B inhibitor LNP023 is in the clinical phase III research stage and is used for the treatment of PNH, IgAN, C3G and other diseases. Therefore, it is necessary to develop new small molecule inhibitors of the complement system Factor B, increase clinical research and verification, and use them in the treatment of various diseases caused by complement abnormalities to provide new treatment methods for unmet clinical needs.
  • the present invention provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
  • R 1 is selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy groups respectively Independently optionally substituted by 1, 2 or 3 Ra ;
  • R 2 is selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R b ;
  • R 3 is selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R c ;
  • R 4 is selected from C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, the C 1-6 alkylthio base, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted by 1, 2, 3 or 4 R d ;
  • Each R 5 is independently selected from D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy groups are independently optionally substituted by 1, 2 or 3 Re ;
  • Each R a is independently selected from D, F, Cl, Br and I;
  • Each R b is independently selected from D, F, Cl, Br and I;
  • Each R c is independently selected from D, F, Cl, Br and I;
  • Each R d is independently selected from D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R;
  • Each Re is independently selected from D, F, Cl, Br and I;
  • Each R is independently selected from D, F, Cl, Br and I;
  • n 0, 1, 2 and 3.
  • the present invention also provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
  • R 1 is selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R a ;
  • R 2 is selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R b ;
  • R 3 is selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R c ;
  • R 4 is selected from C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl, said C 1-6 alkylthio, C 2-6 alkenyl , C 2-6 alkynyl and C 3-6 cycloalkyl are independently optionally substituted by 1, 2, 3 or 4 R d ;
  • Each R 5 is independently selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy groups are each independently optionally substituted by 1, 2 or 3 Re ;
  • Each R a is independently selected from D, F, Cl, Br and I;
  • Each R b is independently selected from D, F, Cl, Br and I;
  • Each R c is independently selected from D, F, Cl, Br and I;
  • Each R d is independently selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy groups are each independently optionally substituted by 1, 2 or 3 R ;
  • Each Re is independently selected from D, F, Cl, Br and I;
  • Each R is independently selected from D, F, Cl, Br and I;
  • n 0, 1, 2 and 3.
  • each of the above R d is independently selected from D, F, Cl, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, and the C 1- 3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R, and other variables are as defined in the present invention.
  • each R d mentioned above is independently selected from F and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R, and other variables are as follows defined by invention.
  • each R d mentioned above is independently selected from F, methyl and ethyl, and the methyl and ethyl are independently optionally substituted by 1, 2 or 3 R.
  • Other variables are as follows defined by the present invention.
  • each R d mentioned above is independently selected from F and methyl, and other variables are as defined in the present invention.
  • each R d mentioned above is independently selected from D, F and Cl, and other variables are as defined in the present invention.
  • each R d mentioned above is independently selected from F, and other variables are as defined in the present invention.
  • each R d mentioned above is independently selected from H and F, and other variables are as defined in the present invention.
  • each R a , each R b , each R c , each Re and each R mentioned above are independently selected from D and F, and other variables are as defined in the present invention.
  • each of the above-mentioned R a , each R b , each R c , each Re and each R are independently selected from D, and other variables are as defined in the present invention.
  • R 1 is selected from C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a , and R a and other variables are as specified in the present invention. definition.
  • R 1 is selected from CH 3 , and the CH 3 is optionally replaced by 1, 2 or 3 R a , and R a and other variables are as defined in the present invention.
  • R 1 is selected from CH 3 and CD 3 , and other variables are as defined in the present invention.
  • R 1 is selected from CH 3 , and other variables are as defined in the present invention.
  • R 2 is selected from C 1-3 alkoxy group, and the C 1-3 alkoxy group is optionally substituted by 1, 2 or 3 R b , and R b and other variables are as follows defined by invention.
  • R 2 is selected from OCH 3 , and the OCH 3 is optionally replaced by 1, 2 or 3 R b , and R b and other variables are as defined in the present invention.
  • R 2 is selected from OCH 3 and OCD 3 , and other variables are as defined in the present invention.
  • R 2 is selected from OCH 3 , and other variables are as defined in the present invention.
  • R 3 is selected from H, F and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R c , and other variables are as in the present invention defined.
  • R 3 is selected from H, F and CH 3 , and other variables are as defined in the present invention.
  • R 3 is selected from H, and other variables are as defined in the present invention.
  • the above R 4 is selected from C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl base, the C 1-6 alkylthio group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl group and 4-6 membered heterocycloalkyl group are independently optionally substituted by 1, 2, 3 or 4 R d substitutions, other variables are as defined in the invention.
  • R 4 is selected from C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl, and the C 1-6 alkyl
  • the thio group, C 2-6 alkenyl group, C 2-6 alkynyl group and C 3-6 cycloalkyl group are each independently optionally substituted by 1, 2, 3 or 4 R d , and other variables are as defined in the present invention.
  • R 4 is selected from C 1-3 alkylthio, C 2-3 alkenyl, C 2-3 alkynyl and C 3-4 cycloalkyl, and the C 1-3 alkyl Thio group, C 2-3 alkenyl, C 2-3 alkynyl and C 3-4 cycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R d , R d and other variables are as in the present invention defined.
  • R 4 is selected from described Each is independently optionally substituted by 1, 2, 3 or 4 R d , and R d and other variables are as defined in the present invention.
  • R 4 is selected from Other variables are as defined in the present invention.
  • R 4 is selected from described Each is independently optionally substituted by 1, 2, 3 or 4 R d , and R d and other variables are as defined in the present invention.
  • R 4 is selected from Other variables are as defined in the present invention.
  • R 4 is selected from C 1-3 alkylthio and C 3-6 cycloalkyl, and the C 1-3 alkylthio and C 3-6 cycloalkyl are independently optional. Choose to be replaced by 1, 2, 3 or 4 R d , and other variables are as defined in the present invention.
  • R 4 is selected from C 1-3 alkylthio and C 3-4 cycloalkyl, and the C 1-3 alkylthio and C 3-4 cycloalkyl are independently optional. Choose to be replaced by 1, 2, 3 or 4 R d , and other variables are as defined in the present invention.
  • R 4 is selected from C 3-4 cycloalkyl, and the C 3-4 cycloalkyl is optionally substituted by 1, 2, 3 or 4 R d , and other variables are as in the present invention defined.
  • R 4 is selected from described Each is independently optionally substituted by 1, 2, 3 or 4 R d , and R d and other variables are as defined in the present invention.
  • R 4 is selected from Other variables are as defined in the present invention.
  • R 4 is selected from Other variables are as defined in the present invention.
  • R 4 is selected from Other variables are as defined in the present invention.
  • R 4 is selected from Other variables are as defined in the present invention.
  • R 4 is selected from Other variables are as defined in the present invention.
  • each of the above R 5 is independently selected from F or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 Re , and other variables are as follows defined by the present invention.
  • each R 5 mentioned above is independently selected from F, and other variables are as defined in the present invention.
  • each R 5 mentioned above is independently selected from H, and other variables are as defined in the present invention.
  • the above m is selected from 0, and other variables are as defined in the present invention.
  • the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (P),
  • R 1 , R 2 , R 3 and R 4 are as defined in the present invention.
  • the above-mentioned compound of formula (I) or formula (P) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (P-1) or a compound of formula (P-2),
  • R 1 , R 2 and R 4 are as defined in the present invention.
  • the above-mentioned formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (P), a compound of formula (P-1) or a compound of formula (P-2), wherein,
  • R 1 is selected from C 1-3 alkyl, which is optionally substituted by 1, 2 or 3 R a ;
  • R 2 is selected from C 1-3 alkoxy, which is optionally substituted by 1, 2 or 3 R b ;
  • R 3 is selected from H
  • R 4 is selected from C 1-3 alkylthio, C 2-3 alkenyl, C 2-3 alkynyl and C 3-4 cycloalkyl, the C 1-3 alkylthio, C 2-3 alkenyl , C 2-3 alkynyl and C 3-4 cycloalkyl are independently optionally substituted by 1, 2, 3 or 4 R d ;
  • Each R a is independently selected from D, F, Cl, Br and I;
  • Each R b is independently selected from D, F, Cl, Br and I;
  • Each R d is independently selected from D, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are respectively independently optionally substituted by 1, 2 or 3 R;
  • Each R is independently selected from D, F, Cl, Br and I.
  • R 4 in the compound of formula (P-1) or the compound of formula (P-2) is as defined for the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof,
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
  • the present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. Furthermore, a pharmaceutically acceptable carrier is also included.
  • the present invention also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of medicaments for treating diseases related to complement factor B.
  • the present invention also provides a method for treating diseases related to complement factor B, comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a mammal (preferably a human) in need of such treatment.
  • the present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the treatment of diseases related to complement factor B.
  • the present invention also provides compounds of the present invention or pharmaceutically acceptable salts thereof for the treatment of diseases associated with complement factor B.
  • the complement factor B-related disease is selected from the group consisting of inflammatory disorders and autoimmune diseases.
  • the pharmaceutically acceptable salt is selected from pharmaceutically acceptable acid addition salts.
  • the pharmaceutically acceptable salt is selected from pharmaceutically acceptable inorganic acid salts, organic acid salts and amino acid salts.
  • the pharmaceutically acceptable salt is selected from formates.
  • stereoisomers and/or tautomers of the compound represented by formula (I) or its pharmaceutically acceptable salt in the present invention are also included in the scope of the present invention.
  • the present invention also provides a synthesis method of the above compound, and its synthesis route is as follows:
  • R 4 is as defined above.
  • R 4 is selected from
  • the invention also provides biological testing methods for the above compounds:
  • the complement system alternative pathway kit is used to determine the inhibitory activity of the test compound against the complement alternative pathway in human serum.
  • the compound of the present invention has obvious inhibitory activity on the activation of human serum bypass pathway.
  • Experimental test method 2 Complement human Factor B protein binding test (TR-FRET method)
  • the TR-FRET method was used to determine the binding activity of the test compound against human complement Factor B protein.
  • the drugs were added to phosphate buffered saline PBS (pH 7.4) starting from 10 ⁇ M and diluted 4 times to 10 concentrations.
  • Biotinylated Factor B 25 nM after the addition of Cy5-labeled probe (75 nM) and europium chelate-labeled streptavidin (Perkin Elmer #AD0060; 0.225 nM) in the absence or presence of different concentrations of test compound. Incubate at room temperature for 2 hours.
  • Time-resolved fluorescence energy transfer (TR-FRET) data were measured using 330 nm as the excitation wavelength and 665 nm as the emission wavelength.
  • the compound of the present invention has significant binding activity to human complement Factor B protein.
  • the compound of the present invention was prepared into a clear solution of 1 mg/mL with an aqueous solution of 0.5% MC (4000cP)/0.5% Tween 80. Rats were fasted overnight before administration, dose: 10 mg/kg, administration method: oral gavage. Collect blood before and 0.25, 0.5, 1, 2, 4, 7, and 24 hours after administration, place it in a heparinized anticoagulant test tube, centrifuge at 7000 rpm (5204g), 4°C, separate plasma, and store at -80°C save. Eat 4 hours after dosing. The LC/MS/MS method was used to determine the content of the test compound in rat plasma after oral administration. Plasma samples were analyzed after pretreatment with precipitated proteins.
  • the compound of the present invention has good oral exposure, long half-life, and excellent pharmacokinetic properties.
  • mice Female C57BL/6J mice, 7-9 weeks old, weighing 17-23 grams; supplier: Shanghai Sipur-Bika Experimental Animal Co., Ltd.
  • LPS lipopolysaccharide
  • Salmonella typhimurium Salmonella typhimurium
  • sterile PBS phosphate buffer pH 7.2-7.4
  • PO gavage
  • Model group (positive control) animals received intraperitoneal LPS and PO administration of vehicle (20% PEG400/10% solutol/70% water).
  • Drug group Samples were collected 4 hours after compound administration (vehicle: 20% PEG400/10% solution/70% water, administration volume: 5 mL/kg, dose: 10 mg/kg).
  • Sample collection 0.3 mL of blood sample was collected from the orbital venous plexus. All blood samples were added into commercial EDTA-K2 anticoagulant tubes with a specification of 1.5 mL (supplier is Jiangsu Kangjian Medical Products Co., Ltd.). After blood samples are collected, within half an hour, centrifuge at 4°C and 3000g for 10 minutes to aspirate the supernatant plasma, quickly transfer it to dry ice, and store it in a -80°C refrigerator for Western blot analysis of downstream C3d protein levels after complement activation.
  • Mouse plasma (5 ⁇ L) + Lysis buffer (lysis buffer, 27.5 ⁇ L) + Loading buffer (loading buffer, 12.5 ⁇ L) + Reducing buffer (reducing buffer, 5 ⁇ L), mix well, incubate at 100°C for 15 minutes, and load the sample
  • the volume is 5 ⁇ L/well, that is, the plasma loading volume per well is 0.5 ⁇ L.
  • the compound of the present invention can or can significantly inhibit complement activation stimulated by LPS.
  • the compound of the present invention has obvious inhibitory activity on the activation of the human serum bypass pathway, and its binding activity to human complement Factor B protein is also significant; It has a moderate plasma protein binding rate in the plasma of various genera, indicating that in the plasma of various genera, the free drug concentration ratio of the compound of the present invention is moderate; it has good pharmacokinetic properties (such as AUC, or F), It has good metabolic stability of liver microsomes; the compound has good permeability; it can significantly inhibit complement activation stimulated by LPS, and can be developed into a new small molecule inhibitor of Factor B of the complement system.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, as well as their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to the present invention. within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” refers to the inability of the double bonds or single bonds of the carbon atoms in the ring to rotate freely.
  • diastereomer refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
  • wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center
  • using straight solid line keys and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line
  • wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key or straight dotted key
  • tautomer or “tautomeric form” refers to the dynamic equilibrium state of isomers with different functional groups at room temperature. balance and can quickly transform into each other. If tautomers are possible (eg in solution), a chemical equilibrium of tautomers can be achieved.
  • proton tautomers also known as proton transfer tautomers
  • proton migration such as keto-enol isomerization and imine-enol isomerization. Amine isomerization.
  • Valence tautomers involve interconversions through the reorganization of some bonding electrons.
  • keto-enol tautomerization is the tautomerization between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Tautomers and mixtures thereof are included within the scope of the present invention.
  • the terms “enriched in an isomer,” “enantiomerically enriched,” “enriched in an enantiomer,” or “enantiomerically enriched” refer to one of the isomers or enantiomers.
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are replaced.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.
  • any variable e.g., R
  • its definition in each instance is independent.
  • said group may optionally be substituted by up to two R's, with independent options for R in each case.
  • R unsubstituted.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • the substituent can be bonded through any atom thereof.
  • a pyridyl group as a substituent can be bonded through any one of the pyridine rings.
  • the carbon atom is attached to the substituted group.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • connection mode of the chemical bond is non-positioned and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will be reduced correspondingly with the number of connected chemical bonds and become the corresponding valence. group.
  • the chemical bond connecting the site to other groups can be a straight solid line bond straight dashed key or wavy lines express.
  • the straight solid line bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in represents the bond through the nitrogen atom in the group Both ends are connected to other groups;
  • the wavy lines in indicate that the phenyl group is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • variable such as R
  • the variable is designated as being substituted on that ring and cannot be substituted on other rings of the polycyclic system, For example Indicates that ring A and ring B are combined rings, and the substituent R 1 is a substituent of ring A, and the substituent R 2 is a substituent of ring B, Indicates that the five-membered ring in the spiro ring system is replaced by n R's.
  • C 1-3 alkyl is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-6 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n - propyl and isopropyl), and the like.
  • C 1-3 alkoxy means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups, etc.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-6 alkylthio means those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through a sulfur atom.
  • the C 1-6 alkylthio group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkane Sulfur group etc.
  • Examples of C 1-6 alkylthio groups include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 , and the like.
  • C 1-3 alkylthio means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through a sulfur atom.
  • the C 1-3 alkylthio group includes C 1-3 , C 1-2 and C 3 alkylthio groups, etc.
  • Examples of C 1-3 alkylthio groups include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 , and the like.
  • C 2-6 alkenyl is used to mean a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond. Can be located anywhere on the group.
  • the C 2-6 alkenyl group includes C 2-4 , C 2-3 , C 4 , C 3 and C 2 alkenyl groups, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 2-6 alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylene, hexadienyl, and the like.
  • C 2-3 alkenyl is used to mean a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, carbon-carbon double bond Can be located anywhere on the group.
  • the C 2-3 alkenyl group includes C 3 and C 2 alkenyl groups; the C 2-3 alkenyl group can be monovalent, divalent or multivalent. Examples of C 2-3 alkenyl groups include, but are not limited to, vinyl, propenyl, and the like.
  • C 2-6 alkynyl is used to mean a straight or branched chain of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond.
  • the carbon-carbon triple bond can be located at any position on the group.
  • the C 2-6 alkynyl group includes C 2-4 , C 2-3 , C 4 , C 3 and C 2 alkynyl groups, etc. It can be monovalent, bivalent or polyvalent. Examples of C 2-6 alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
  • C 2-3 alkynyl is used to mean a straight-chain or branched hydrocarbon group composed of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond. Can be located anywhere on the group. It can be monovalent, bivalent or polyvalent.
  • the C 2-3 alkynyl group includes C 3 and C 2 alkynyl groups. Examples of C 2-3 alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.
  • C 3-6 cycloalkyl means a saturated monocyclic hydrocarbon group composed of 3 to 6 carbon atoms, and the C 3-6 cycloalkyl group includes C 3-4 , C 3- 5.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • C 3-4 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 4 carbon atoms, which is a single ring system, and the C 3-4 cycloalkyl group includes C 3 and C 4 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-4 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl.
  • 3-6-membered heterocyclyl by itself or in combination with other terms respectively represents a saturated or partially unsaturated monocyclic cyclic group consisting of 3 to 6 ring atoms, where 1, 2, and 3 Or 4 ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S ( O) p , p is 1 or 2). Furthermore, in the case of the "3-6 membered heterocyclyl", the heteroatom may occupy the attachment position of the heterocyclyl to the rest of the molecule.
  • the 3-6-membered heterocyclic groups include 4-6-membered, 5-6-membered, 4-membered, 5-membered and 6-membered heterocyclic groups, etc.
  • Examples of 3-6 membered heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including Tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl) Aldinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc
  • 4-6 membered heterocycloalkyl refers to a fully saturated 4-6 membered heterocyclyl.
  • the 4-6-membered heterocycloalkyl group includes 4-5-membered, 5-6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups, etc.
  • Non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thibutanyl groups
  • examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, and pyrrolidine.
  • 6-membered heterocycloalkyl examples include but are not limited to piperidinyl, tetrahydropyrazolyl Pyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithiane base, 1,4-dithianyl.
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , also include any range from n to n+m, for example, C1-12 includes C1-6 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; similarly, n yuan to n The +m member indicates that the number of atoms in the ring is n to n+m.
  • a 3-12 membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, and a 9-membered ring.
  • 3-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, etc.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
  • the structure of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute structure of the compound, For configuration, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal.
  • the light source is CuK ⁇ radiation.
  • the scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
  • the solvent used in the present invention is commercially available.
  • Compounds are named according to conventional naming principles in the field or use For software naming, commercially available compounds adopt supplier catalog names.
  • Figure 1 Experimental results of LPS-induced complement activation in mouse PD model.
  • Benzylamine (194.62g, 1.82mol) was slowly added to water (850mL) dissolved with acetic acid (103.88mL, 1.82mol). The reaction system was cooled to 0-10°C, and then 1,3-acetone dicarboxylic acid (265.36g, 1.82mol) was slowly added in batches, and the reaction solution was allowed to react at 0°C for 0.5 hours.
  • a solution of compound Ma (170g, 908.15mmol) dissolved in dioxane (850mL) was slowly added to the reaction system, the reaction solution was slowly returned to room temperature, and then reacted at 45°C for 12 hours.
  • Ethyl mercaptan (8.94g, 143.82mmol) was dissolved in tetrahydrofuran (60mL) solution, and sodium hydride (6.14g, 127.84mmol, 50% purity) was added under nitrogen protection. The reaction solution was stirred at 20°C for 0.5 hours. Then, a solution of compound 1-2 (6.4 g, 15.98 mmol) dissolved in N,N-dimethylformamide (60 mL) was slowly added to the reaction solution. The reaction solution was stirred at 70°C for 2 hours. Add 100 mL of saturated ammonium chloride aqueous solution to the reaction solution at 0°C to quench the reaction, and then add 100 mL of water to dilute.
  • Compound 1A has a shorter retention time in the chiral chromatography column than 1B, and compound 1B has a longer retention time in the chiral chromatography column than 1A.
  • Compound 2A has a shorter retention time in the chiral chromatography column than 2B, and compound 2B has a longer retention time in the chiral chromatography column than 2A.
  • N,N-dimethylformamide dimethyl acetal (614.83 mg, 5.16 mmol) was added to a solution of compound 3-3 (0.62 g, 1.72 mmol) in methanol (25 mL), and the temperature was raised to 60°C for 16 hours.
  • the reaction solution was cooled to room temperature, diluted with 30 mL of water, and then extracted with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 3-4.
  • Compound 3 was obtained by chiral column separation (chromatographic column: Daicel ChiralPak IC 250 ⁇ 30mm., 10 ⁇ m, mobile phase: A: carbon dioxide, B: isopropyl alcohol (0.1% ammonia), method: B: 40%-40%) Compound 3A and Compound 3B.
  • Compound 3A has a shorter retention time in the chiral chromatography column than 3B, and compound 3B has a longer retention time in the chiral chromatography column than 3A.
  • Experimental purpose Use SPR method to detect the kinetic constants and affinity of the binding between the test compound and human complement factor B.
  • EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • NHS N-hydroxysulfosuccinimide sodium salt
  • each channel serves as the reference channel and only performs surface activation and deactivation without injecting complement factor B protein solution.
  • All sample storage solutions were diluted with running buffer (PBST), and all samples were serially diluted 6 points in duplicate in 2-fold wells. Transfer the prepared samples to the detection plate according to the program settings, and place the detection plate in the sample compartment of Biacore 8K. Run the detection program, and the samples are injected into each channel of the chip sequentially according to the program.
  • PBST running buffer
  • the binding time is 120s, the dissociation time is 600s, and the flow rate is 30 ⁇ L/min.
  • the binding activity of the test compounds to human complement Factor B protein is shown in Table 1. Among them, A represents: IC 50 value ⁇ 100nM; B represents: 100nM ⁇ IC 50 value ⁇ 1000nM; C represents: IC 50 value > 1000nM.
  • Table 1 In vitro human complement Factor B protein binding activity screening test results of the compounds of the present invention
  • the compound of the present invention has significant binding activity to human complement Factor B protein.
  • Experimental animals female C57BL/6J mice, 7-9 weeks old, weighing 17-23 grams; supplier: Shanghai Sipur-Bika Experimental Animal Co., Ltd.
  • LPS lipopolysaccharide
  • Escherichia coli Escherichia coli
  • sterile PBS phosphate buffer pH 7.2-7.4
  • Normal mouse group negative control: animals received an intraperitoneal injection of 100 ⁇ L of sterile PBS, and vehicle alone was administered by gavage (IO).
  • Model group positive control: animals received intraperitoneal LPS and PO administration of vehicle (20% PEG400/10% solutol/70% water).
  • Drug group Samples were collected 4 hours after compound administration (vehicle: 20% PEG400/10% solution/70% water, administration volume: 5 mL/kg, dose: 10 mg/kg).
  • Sample collection 0.3 mL of blood sample was collected from the orbital venous plexus. All blood samples were added into commercial EDTA-K2 anticoagulant tubes with a specification of 1.5 mL (supplier is Jiangsu Kangjian Medical Products Co., Ltd.). After blood samples are collected, within half an hour, centrifuge at 4°C and 3000g for 10 minutes to aspirate the supernatant plasma, quickly transfer it to dry ice, and store it in a -80°C refrigerator for Western blot analysis of downstream C3d protein levels after complement activation.
  • the C3d protein level in the serum of mice in the model group increased by 60% to 90% compared with the normal group.
  • the C3d protein level in the serum of mice in each drug group increased by 60% to 90%.
  • Experimental purpose Use equilibrium dialysis method to evaluate the protein binding rate of the compound of the present invention in the plasma of CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys and humans.
  • test compound was diluted into the plasma of the above five species with dialysis buffer to prepare a sample with a final concentration of 2 ⁇ M.
  • the sample was then added to a 96-well equilibrium dialysis device and dialyzed with phosphate buffer solution at 37°C. 4 hours.
  • the experiment used warfarin as a control compound.
  • the experimental results are shown in Table 2.
  • the compound of the present invention has a moderate plasma protein binding rate in the plasma of various genera, which indicates that in the plasma of the above-mentioned various genera, the free drug concentration ratio of the compound of the present invention is moderate and has good pharmaceutical properties.
  • Liver microsomes purchased from Corning or Xenotech, stored in -80°C refrigerator; reduced nicotinamide adenine dinucleotide phosphate (NADPH), supplier: Chem-impex international, product number: 00616; control compounds: testosterone, diclofenac , propafenone.
  • NADPH reduced nicotinamide adenine dinucleotide phosphate
  • T60 incubation plate Prepare two 96-well incubation plates, named T60 incubation plate and NCF60 incubation plate respectively.
  • microsomal working solution live microsomal protein concentration is 0.56 mg/mL
  • test product or control compound working solution After the pre-incubation, add 5 ⁇ L of test product or control compound working solution to the T60 incubation plate and NCF60 incubation plate respectively, and mix well. Add 50 ⁇ L potassium phosphate buffer to each well of the NCF60 incubation plate to start the reaction; add 180 ⁇ L stop solution (containing 200ng/mL tolbutamide (tolbutamide) and 200ng/mL labetalol (labetalol)) to the T0 stop plate. Acetonitrile solution) and 6 ⁇ L of NADPH regeneration system working solution, take 54 ⁇ L of sample from the T60 incubation plate to the T0 stop plate (TO sample generation).
  • stop solution containing 200ng/mL tolbutamide (tolbutamide) and 200ng/mL labetalol (labetalol)
  • stop solution acetonitrile solution containing 200ng/mL tolbutamide and 200ng/mL labetalol
  • test compound was mixed with 5% DMSO/10% polyethylene glycol-15 hydroxystearate/85% water, vortexed and ultrasonicated to prepare a 0.2 mg/mL clear solution, which was filtered through a microporous membrane for later use.
  • Select Balb/c male mice of 18 to 20 grams, and administer the candidate compound solution intravenously at a dose of 1 mg/kg; administer the test compound solution orally at a dose of 10 mg/kg.
  • C 0 instantaneous required concentration after intravenous injection
  • C max The highest value of blood drug concentration after administration
  • T max the time required to reach the peak drug concentration after administration
  • T 1/2 the time required for the blood drug concentration to drop by half
  • V dss apparent volume of distribution, refers to The proportional constant between the amount of drug in the body and the blood drug concentration when the drug reaches dynamic equilibrium in the body.
  • the compound of the present invention exhibits a longer half-life and higher drug exposure, and has good pharmacokinetic properties in vivo.
  • the dose is 1mpk, the concentration is 0.20mg/mL, the solvent is 20% PEG400/10% solution/70% water; for oral administration (PO), the dose is 10mpk, the concentration is 1mg/mL, the solvent It is 20%PEG400/10%solutol/70%water.
  • Plasma: dichlorvos solution 40:1.
  • the dichlorvos solution is a 40mM dichlorvos acetonitrile/water (1:1) solution.
  • the solution is heated at 4°C and 3000g. Centrifuge for 10 minutes to aspirate the supernatant plasma, quickly place it in dry ice, and store it in a -80°C refrigerator for LC-MS/MS analysis.
  • the compound of the present invention exhibits a longer half-life and higher oral plasma exposure, and has good pharmacokinetic properties.
  • Cell culture uses MEM (minimum essential medium) supplemented with 2mM L-glutamine, 10% fetal bovine serum (FBS), 100U/mL penicillin-G, and 100 ⁇ g/mL streptomycin. Cell culture conditions are 37 ⁇ 1°C, 5% CO2 and saturated humidity. When the cells grow to 80-90% density, add trypsin (0.05%, w/v)/EDTA (0.02%, w/v) digestion solution to digest the cells and then seed the plate. Cells were seeded in BD Falcon Transwell-96 well plates at a seeding density of 1 ⁇ 10 5 cells/cm 2 . The cells were cultured in a carbon dioxide incubator for 22 days and then used for transport experiments.
  • MEM minimum essential medium
  • FBS fetal bovine serum
  • This project uses Hank's balanced salt buffer (pH 7.40 ⁇ 0.05) containing 10mM HEPES as the transport buffer.
  • the test compound and the positive drug digoxin were tested for bidirectional transport at a concentration of 2 ⁇ M, with two parallel samples each, and the apical to basal (AB) transport of fenoterol and propranolol.
  • the concentration of DMSO in the incubation system is controlled below 1%.
  • After adding the sample place the cell plate and incubate it for 120 minutes at 37 ⁇ 1°C, 5% CO2 and saturated humidity. All samples are vortexed and shaken at 3220rpm and 20°C. Centrifuge for 20 minutes, dilute the control substance and test substance with ultrapure water 1:1 (v:v) and store at 4°C. Analyze and test using liquid chromatography tandem mass spectrometry (LC/MS/MS).
  • LC/MS/MS liquid chromatography tandem mass spectrometry
  • the compound of the present invention has good permeability.

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Abstract

Disclosed in the present invention are a series of nitrogen-containing bridged heterocyclic compounds and a preparation method therefor, and particularly a compound represented by formula (I) and a pharmaceutically acceptable salt thereof. In particular, the present invention also relates to a preparation method for the compound, a pharmaceutical composition, and a use thereof in treating inflammatory diseases.

Description

一系列含氮桥杂环化合物及其制备方法A series of nitrogen-containing bridged heterocyclic compounds and preparation methods thereof
相关申请的交叉引用Cross-references to related applications
本申请要求于2022年08月29日向中国国家知识产权局提交的第202211064029.7号中国发明专利申请、2022年10月09日向中国国家知识产权局提交的第202211231001.8号中国发明专利申请、和2023年08月22日向中国国家知识产权局提交的第2023110663471号中国发明专利申请的优先权和权益，所述申请公开的全部内容通过引用整体并入本文中。This application requires the Chinese Invention Patent Application No. 202211064029.7 submitted to the State Intellectual Property Office of China on August 29, 2022, the Chinese Invention Patent Application No. 202211231001.8 submitted to the State Intellectual Property Office of China on October 9, 2022, and the Chinese Invention Patent Application No. 202211231001.8 submitted to the State Intellectual Property Office of China on October 9, 2023. Priority and rights to the Chinese invention patent application No. 2023110663471 submitted to the State Intellectual Property Office of China on September 22. The entire disclosure of the application is incorporated herein by reference in its entirety.
技术领域Technical field
本发明涉及一系列含氮桥杂环化合物及其制备方法，具体涉及式(I)所示化合物及其药学上可接受的盐。The present invention relates to a series of nitrogen-containing bridged heterocyclic compounds and their preparation methods, specifically to the compounds represented by formula (I) and their pharmaceutically acceptable salts.
背景技术Background technique
补体系统统由超过50种可精确调控的蛋白质组成，是人体固有免疫的重要部分，且是联通固有免疫和获得性免疫的桥梁。补体系统主要通过三条通路激活：经典通路(classical pathway，CP)、凝集素通路(lectin pathway，LP)以及旁路通路(alternative pathway，AP)。The complement system consists of more than 50 proteins that can be precisely regulated. It is an important part of the human body's innate immunity and serves as a bridge between innate immunity and acquired immunity. The complement system is mainly activated through three pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP).
这3条激活途径均以形成C3转化酶和C5转化酶为中心，通过裂解C3和C5产生相应的生物活性片段，进一步放大补体反应，这些片段修饰靶表面，可促进吞噬、炎症和免疫调节等过程。其中，从接触激活起始物到生成C3转化酶(并裂解C3)可被当作这些激活途径的前端反应。尽管这些激活途径的前端反应各异，但具有共同的末端通路，即生成C5转化酶，通过裂解C5形成C5b片段，依次与C6、C7、C8、C9反应，最终形成攻膜复合物(membrane attack complex，MAC)，发挥溶细胞效应。These three activation pathways are centered on the formation of C3 convertase and C5 convertase. They produce corresponding bioactive fragments by cleaving C3 and C5 to further amplify the complement reaction. These fragments modify the target surface and can promote phagocytosis, inflammation, immune regulation, etc. process. Among them, the reaction from contact with the activation starter to the generation of C3 convertase (and cleavage of C3) can be regarded as the front-end reaction of these activation pathways. Although the front-end reactions of these activation pathways are different, they have a common terminal pathway, that is, the generation of C5 convertase, which cleaves C5 to form a C5b fragment, which reacts with C6, C7, C8, and C9 in sequence, and finally forms a membrane attack complex. complex, MAC), exerting a cytolytic effect.
补体Factor B作用于AP通路，抑制Factor B活性能够阻止AP通路激活，且不干扰CP和LP通路，能够降低因补体系统抑制增加导致的感染风险。目前尚无小分子Factor B抑制剂上市，Novartis的factor B抑制剂LNP023处于临床III期研究阶段，用于PNH、IgAN、C3G等疾病的治疗。因此，有必要开发新型补体系统Factor B小分子抑制剂，增加临床研究和验证并用于补体异常导致的各种疾病的治疗，为未满足临床需求提供新的治疗手段。Complement Factor B acts on the AP pathway. Inhibiting Factor B activity can prevent the activation of the AP pathway without interfering with the CP and LP pathways, and can reduce the risk of infection caused by increased inhibition of the complement system. There are currently no small molecule Factor B inhibitors on the market. Novartis' factor B inhibitor LNP023 is in the clinical phase III research stage and is used for the treatment of PNH, IgAN, C3G and other diseases. Therefore, it is necessary to develop new small molecule inhibitors of the complement system Factor B, increase clinical research and verification, and use them in the treatment of various diseases caused by complement abnormalities to provide new treatment methods for unmet clinical needs.
发明内容Contents of the invention
本发明提供了式(I)所示化合物或其药学上可接受的盐，
The present invention provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
其中，in,
R1选自H、D、F、Cl、Br、I、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别 独立地任选被1、2或3个Ra取代；R 1 is selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy groups respectively Independently optionally substituted by 1, 2 or 3 Ra ;
R2选自H、D、F、Cl、Br、I、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rb取代；R 2 is selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R b ;
R3选自H、D、F、Cl、Br、I、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rc取代；R 3 is selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R c ;
R4选自C1-6烷硫基、C2-6烯基、C2-6炔基、C3-6环烷基和3-6元杂环基，所述C1-6烷硫基、C2-6烯基、C2-6炔基、C3-6环烷基和3-6元杂环基分别独立地任选被1、2、3或4个Rd取代；R 4 is selected from C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, the C 1-6 alkylthio base, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted by 1, 2, 3 or 4 R d ;
各R5分别独立地选自D、F、Cl、Br、I、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Re取代；Each R 5 is independently selected from D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy groups are independently optionally substituted by 1, 2 or 3 Re ;
各Ra分别独立地选自D、F、Cl、Br和I；Each R a is independently selected from D, F, Cl, Br and I;
各Rb分别独立地选自D、F、Cl、Br和I；Each R b is independently selected from D, F, Cl, Br and I;
各Rc分别独立地选自D、F、Cl、Br和I；Each R c is independently selected from D, F, Cl, Br and I;
各Rd分别独立地选自D、F、Cl、Br、I、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个R取代；Each R d is independently selected from D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R;
各Re分别独立地选自D、F、Cl、Br和I；Each Re is independently selected from D, F, Cl, Br and I;
各R分别独立地选自D、F、Cl、Br和I；Each R is independently selected from D, F, Cl, Br and I;
m选自0、1、2和3。m is selected from 0, 1, 2 and 3.
本发明还提供了式(I)所示化合物或其药学上可接受的盐，
The present invention also provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
其中，in,
R1选自H、D、F、Cl、Br、I、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Ra取代；R 1 is selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R a ;
R2选自H、D、F、Cl、Br、I、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rb取代；R 2 is selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R b ;
R3选自H、D、F、Cl、Br、I、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rc取代；R 3 is selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R c ;
R4选自C1-6烷硫基、C2-6烯基、C2-6炔基和C3-6环烷基，所述C1-6烷硫基、C2-6烯基、C2-6炔基和C3-6环烷基分别独立地任选被1、2、3或4个Rd取代；R 4 is selected from C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl, said C 1-6 alkylthio, C 2-6 alkenyl , C 2-6 alkynyl and C 3-6 cycloalkyl are independently optionally substituted by 1, 2, 3 or 4 R d ;
各R5分别独立地选自H、D、F、Cl、Br、I、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1- 3烷氧基分别独立地任选被1、2或3个Re取代； Each R 5 is independently selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy groups are each independently optionally substituted by 1, 2 or 3 Re ;
各Ra分别独立地选自D、F、Cl、Br和I；Each R a is independently selected from D, F, Cl, Br and I;
各Rb分别独立地选自D、F、Cl、Br和I；Each R b is independently selected from D, F, Cl, Br and I;
各Rc分别独立地选自D、F、Cl、Br和I；Each R c is independently selected from D, F, Cl, Br and I;
各Rd分别独立地选自H、D、F、Cl、Br、I、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1- 3烷氧基分别独立地任选被1、2或3个R取代；Each R d is independently selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy groups are each independently optionally substituted by 1, 2 or 3 R ;
各Re分别独立地选自D、F、Cl、Br和I；Each Re is independently selected from D, F, Cl, Br and I;
各R分别独立地选自D、F、Cl、Br和I；Each R is independently selected from D, F, Cl, Br and I;
m选自0、1、2和3。m is selected from 0, 1, 2 and 3.
在本发明的一些方案中，上述各Rd分别独立地选自D、F、Cl、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个R取代，其他变量如本发明所定义。In some aspects of the invention, each of the above R d is independently selected from D, F, Cl, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, and the C 1- 3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R, and other variables are as defined in the present invention.
在本发明的一些方案中，上述各Rd分别独立地选自F和C1-3烷基，所述C1-3烷基任选被1、2或3个R取代，其他变量如本发明所定义。In some embodiments of the present invention, each R d mentioned above is independently selected from F and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R, and other variables are as follows defined by invention.
在本发明的一些方案中，上述各Rd分别独立地选自F、甲基和乙基，所述甲基和乙基分别独立地任选被1、2或3个R取代，其他变量如本发明所定义。In some aspects of the present invention, each R d mentioned above is independently selected from F, methyl and ethyl, and the methyl and ethyl are independently optionally substituted by 1, 2 or 3 R. Other variables are as follows defined by the present invention.
在本发明的一些方案中，上述各Rd分别独立地选自F和甲基，其他变量如本发明所定义。In some aspects of the present invention, each R d mentioned above is independently selected from F and methyl, and other variables are as defined in the present invention.
在本发明的一些方案中，上述各Rd分别独立地选自D、F和Cl，其他变量如本发明所定义。In some solutions of the present invention, each R d mentioned above is independently selected from D, F and Cl, and other variables are as defined in the present invention.
在本发明的一些方案中，上述各Rd分别独立地选自F，其他变量如本发明所定义。In some solutions of the present invention, each R d mentioned above is independently selected from F, and other variables are as defined in the present invention.
在本发明的一些方案中，上述各Rd分别独立地选自H和F，其他变量如本发明所定义。在本发明的一些方案中，上述各Ra、各Rb、各Rc、各Re和各R分别独立地选自D和F，其他变量如本发明所定义。In some solutions of the present invention, each R d mentioned above is independently selected from H and F, and other variables are as defined in the present invention. In some solutions of the present invention, each R a , each R b , each R c , each Re and each R mentioned above are independently selected from D and F, and other variables are as defined in the present invention.
在本发明的一些方案中，上述各Ra、各Rb、各Rc、各Re和各R分别独立地选自D，其他变量如本发明所定义。In some solutions of the present invention, each of the above-mentioned R a , each R b , each R c , each Re and each R are independently selected from D, and other variables are as defined in the present invention.
在本发明的一些方案中，上述R1选自C1-3烷基，所述C1-3烷基任选被1、2或3个Ra取代，Ra及其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 1 is selected from C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a , and R a and other variables are as specified in the present invention. definition.
在本发明的一些方案中，上述R1选自CH3，所述CH3任选被1、2或3个Ra取代，Ra及其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 1 is selected from CH 3 , and the CH 3 is optionally replaced by 1, 2 or 3 R a , and R a and other variables are as defined in the present invention.
在本发明的一些方案中，上述R1选自CH3和CD3，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 1 is selected from CH 3 and CD 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R1选自CH3，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 1 is selected from CH 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R2选自C1-3烷氧基，所述C1-3烷氧基任选被1、2或3个Rb取代，Rb及其他变量如本发明所定义。In some aspects of the invention, the above-mentioned R 2 is selected from C 1-3 alkoxy group, and the C 1-3 alkoxy group is optionally substituted by 1, 2 or 3 R b , and R b and other variables are as follows defined by invention.
在本发明的一些方案中，上述R2选自OCH3，所述OCH3任选被1、2或3个Rb取代，Rb及其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 2 is selected from OCH 3 , and the OCH 3 is optionally replaced by 1, 2 or 3 R b , and R b and other variables are as defined in the present invention.
在本发明的一些方案中，上述R2选自OCH3和OCD3，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 2 is selected from OCH 3 and OCD 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R2选自OCH3，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 2 is selected from OCH 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R3选自H、F和C1-3烷基，所述C1-3烷基任选被1、2或3个Rc取代，其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned R 3 is selected from H, F and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R c , and other variables are as in the present invention defined.
在本发明的一些方案中，上述R3选自H、F和CH3，其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 3 is selected from H, F and CH 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R3选自H，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 3 is selected from H, and other variables are as defined in the present invention.
在本发明的一些方案中，上述R4选自C1-6烷硫基、C2-6烯基、C2-6炔基、C3-6环烷基和4-6元杂环烷基，所述C1-6烷硫基、C2-6烯基、C2-6炔基、C3-6环烷基和4-6元杂环烷基分别独立地任选被1、2、3或4个Rd取代，其他变量如本发明所定义。In some aspects of the invention, the above R 4 is selected from C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl base, the C 1-6 alkylthio group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl group and 4-6 membered heterocycloalkyl group are independently optionally substituted by 1, 2, 3 or 4 R d substitutions, other variables are as defined in the invention.
在本发明的一些方案中，上述R4选自C1-6烷硫基、C2-6烯基、C2-6炔基和C3-6环烷基，所述C1-6烷硫基、C2-6烯基、C2-6炔基和C3-6环烷基分别独立地任选被1、2、3或4个Rd取代，其他变量如本发明所定义。In some aspects of the invention, the above R 4 is selected from C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl, and the C 1-6 alkyl The thio group, C 2-6 alkenyl group, C 2-6 alkynyl group and C 3-6 cycloalkyl group are each independently optionally substituted by 1, 2, 3 or 4 R d , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R4选自C1-3烷硫基、C2-3烯基、C2-3炔基和C3-4环烷基，所述C1-3烷硫基、C2-3烯基、C2-3炔基和C3-4环烷基分别独立地任选被1、2、3或4个Rd取代，Rd及其他变量如本发明所定义。In some aspects of the invention, the above R 4 is selected from C 1-3 alkylthio, C 2-3 alkenyl, C 2-3 alkynyl and C 3-4 cycloalkyl, and the C 1-3 alkyl Thio group, C 2-3 alkenyl, C 2-3 alkynyl and C 3-4 cycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R d , R d and other variables are as in the present invention defined.
在本发明的一些方案中，上述R4选自所述 分别独立地任选被1、2、3或4个Rd取代，Rd及其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 4 is selected from described Each is independently optionally substituted by 1, 2, 3 or 4 R d , and R d and other variables are as defined in the present invention.
在本发明的一些方案中，上述R4选自其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 4 is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述R4选自所述 分别独立地任选被1、2、3或4个Rd取代，Rd及其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 4 is selected from described Each is independently optionally substituted by 1, 2, 3 or 4 R d , and R d and other variables are as defined in the present invention.
在本发明的一些方案中，上述R4选自 其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 4 is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述R4选自C1-3烷硫基和C3-6环烷基，所述C1-3烷硫基和C3-6环烷基分别独立地任选被1、2、3或4个Rd取代，其他变量如本发明所定义。In some aspects of the invention, the above-mentioned R 4 is selected from C 1-3 alkylthio and C 3-6 cycloalkyl, and the C 1-3 alkylthio and C 3-6 cycloalkyl are independently optional. Choose to be replaced by 1, 2, 3 or 4 R d , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R4选自C1-3烷硫基和C3-4环烷基，所述C1-3烷硫基和C3-4环烷基分别独立地任选被1、2、3或4个Rd取代，其他变量如本发明所定义。In some aspects of the invention, the above R 4 is selected from C 1-3 alkylthio and C 3-4 cycloalkyl, and the C 1-3 alkylthio and C 3-4 cycloalkyl are independently optional. Choose to be replaced by 1, 2, 3 or 4 R d , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R4选自C3-4环烷基，所述C3-4环烷基任选被1、2、3或4个Rd取代，其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 4 is selected from C 3-4 cycloalkyl, and the C 3-4 cycloalkyl is optionally substituted by 1, 2, 3 or 4 R d , and other variables are as in the present invention defined.
在本发明的一些方案中，上述R4选自所述分别独立地任选被1、2、3或4个Rd取代，Rd及其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 4 is selected from described Each is independently optionally substituted by 1, 2, 3 or 4 R d , and R d and other variables are as defined in the present invention.
在本发明的一些方案中，上述R4选自其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 4 is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述R4选自其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 4 is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述R4选自其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 4 is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述R4选自其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 4 is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述R4选自其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 4 is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述各R5分别独立地选自F或C1-3烷基，所述C1-3烷基任选被1、2或3个Re取代，其他变量如本发明所定义。In some aspects of the present invention, each of the above R 5 is independently selected from F or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 Re , and other variables are as follows defined by the present invention.
在本发明的一些方案中，上述各R5分别独立地选自F，其他变量如本发明所定义。In some aspects of the present invention, each R 5 mentioned above is independently selected from F, and other variables are as defined in the present invention.
在本发明的一些方案中，上述各R5分别独立地选自H，其他变量如本发明所定义。In some aspects of the present invention, each R 5 mentioned above is independently selected from H, and other variables are as defined in the present invention.
在本发明的一些方案中，上述m选自0，其他变量如本发明所定义。In some solutions of the present invention, the above m is selected from 0, and other variables are as defined in the present invention.
在本发明的一些方案中，上述式(I)化合物或其药学上可接受的盐，其选自式(P)化合物，
In some aspects of the present invention, the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (P),
其中，R1、R2、R3和R4如本发明所定义。Among them, R 1 , R 2 , R 3 and R 4 are as defined in the present invention.
在本发明的一些方案中，上述式(I)或式(P)化合物或其药学上可接受的盐，其选自式(P-1)化合物或式(P-2)化合物，
In some aspects of the present invention, the above-mentioned compound of formula (I) or formula (P) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (P-1) or a compound of formula (P-2),
其中，R1、R2和R4如本发明所定义。Among them, R 1 , R 2 and R 4 are as defined in the present invention.
在本发明的一些方案中，上述式(I)或其药学上可接受的盐，其选自式(P)化合物、式(P-1)化合物或式(P-2)化合物，其中，In some aspects of the present invention, the above-mentioned formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (P), a compound of formula (P-1) or a compound of formula (P-2), wherein,
R1选自C1-3烷基，所述C1-3烷基任选被1、2或3个Ra取代；R 1 is selected from C 1-3 alkyl, which is optionally substituted by 1, 2 or 3 R a ;
R2选自C1-3烷氧基，所述C1-3烷氧基任选被1、2或3个Rb取代；R 2 is selected from C 1-3 alkoxy, which is optionally substituted by 1, 2 or 3 R b ;
R3选自H；R 3 is selected from H;
R4选自C1-3烷硫基、C2-3烯基、C2-3炔基和C3-4环烷基，所述C1-3烷硫基、C2-3烯基、C2-3炔基和C3-4环烷基分别独立地任选被1、2、3或4个Rd取代；R 4 is selected from C 1-3 alkylthio, C 2-3 alkenyl, C 2-3 alkynyl and C 3-4 cycloalkyl, the C 1-3 alkylthio, C 2-3 alkenyl , C 2-3 alkynyl and C 3-4 cycloalkyl are independently optionally substituted by 1, 2, 3 or 4 R d ;
各Ra分别独立地选自D、F、Cl、Br和I；Each R a is independently selected from D, F, Cl, Br and I;
各Rb分别独立地选自D、F、Cl、Br和I；Each R b is independently selected from D, F, Cl, Br and I;
各Rd分别独立地选自D、F、Cl、Br、I、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个R取代；Each R d is independently selected from D, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are respectively independently optionally substituted by 1, 2 or 3 R;
各R分别独立地选自D、F、Cl、Br和I。Each R is independently selected from D, F, Cl, Br and I.
在本发明的一些方案中，式(P-1)化合物或式(P-2)化合物中的R4如上述式(I)化合物或其药学上可接受的盐所定义。In some embodiments of the present invention, R 4 in the compound of formula (P-1) or the compound of formula (P-2) is as defined for the compound of formula (I) or a pharmaceutically acceptable salt thereof.
本发明还有一些方案由所述变量任意组合而来。There are also some solutions of the present invention derived from any combination of the above-mentioned variables.
本发明还提供了下列所示化合物或其药学上可接受的盐，

The present invention also provides the following compounds or pharmaceutically acceptable salts thereof,

在本发明的一些方案中，上述化合物或其药学上可接受的盐选自，




In some aspects of the invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,




本发明还提供一种药物组合物，其含有治疗有效量的本发明的化合物或其药学上可接受的盐。进一步地，还包括药学上可接受的载体。The present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. Furthermore, a pharmaceutically acceptable carrier is also included.
本发明还提供了上述化合物或其药学上可接受的盐在制备治疗与补体因子B相关疾病的药物中的应用。The present invention also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of medicaments for treating diseases related to complement factor B.
本发明还提供治疗与补体因子B相关疾病的方法，包括对需要该治疗的哺乳动物(优选人类)给予治疗有效量的本发明的化合物或其药学上可接受的盐。 The present invention also provides a method for treating diseases related to complement factor B, comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a mammal (preferably a human) in need of such treatment.
本发明还提供本发明的化合物或其药学上可接受的盐在治疗与补体因子B相关疾病中的应用。The present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the treatment of diseases related to complement factor B.
本发明还提供用于治疗与补体因子B相关疾病的本发明的化合物或其药学上可接受的盐。The present invention also provides compounds of the present invention or pharmaceutically acceptable salts thereof for the treatment of diseases associated with complement factor B.
本发明的一些方案中，所述补体因子B相关疾病选自炎性障碍和自身免疫性疾病。In some aspects of the invention, the complement factor B-related disease is selected from the group consisting of inflammatory disorders and autoimmune diseases.
本发明的一些方案中，所述药学上可接受的盐选自药学上可接受的酸加成盐。In some embodiments of the present invention, the pharmaceutically acceptable salt is selected from pharmaceutically acceptable acid addition salts.
本发明的一些方案中，所述药学上可接受的盐选自药学上可接受的无机酸盐、有机酸盐和氨基酸盐。In some embodiments of the present invention, the pharmaceutically acceptable salt is selected from pharmaceutically acceptable inorganic acid salts, organic acid salts and amino acid salts.
本发明的一些方案中，所述药学上可接受的盐选自甲酸盐。In some embodiments of the invention, the pharmaceutically acceptable salt is selected from formates.
本发明中所述式(I)所示化合物或其药学上可接受的盐的立体异构体和/或互变异构体也包含在本发明范围内。The stereoisomers and/or tautomers of the compound represented by formula (I) or its pharmaceutically acceptable salt in the present invention are also included in the scope of the present invention.
本发明还提供了上述化合物的合成方法，其合成路线如下：The present invention also provides a synthesis method of the above compound, and its synthesis route is as follows:
合成路线1：
Synthesis route 1:
其中，R4如上所定义。Where, R 4 is as defined above.
在本发明的一些方案中，R4选自 In some aspects of the invention, R 4 is selected from
本发明还提供了上述化合物的生物试验测试方法：The invention also provides biological testing methods for the above compounds:
实验测试方法1：Wieslab补体旁路通路活化抑制(酶活测试)Experimental test method 1: Wieslab complement alternative pathway activation inhibition (enzyme activity test)
实验目的：Purpose:
通过补体系统旁路通路试剂盒，对待测化合物针对人血清中补体旁路通路的抑制活性的测定。pass The complement system alternative pathway kit is used to determine the inhibitory activity of the test compound against the complement alternative pathway in human serum.
实验方案：Experimental program:
用稀释液将血清进行稀释(1：23)。向稀释的血清中加入药物，8个浓度梯度，最高10mM或50mM，5倍梯度稀释。室温孵育15min。将化合物和血清混合物加入试剂盒提供的96孔板(100μL/孔)，在37度激活1小时。用洗涤缓冲液清洗三遍。加入试剂盒提供的检测抗体(100μL)在室温进行孵育30min。用洗涤缓冲液清洗三遍。加入底物(100μL)在室温进行孵育30min。酶标仪405nM处检测吸光度。Dilute the serum with diluent (1:23). Add the drug to the diluted serum in 8 concentration gradients, up to 10mM or 50mM, in 5-fold gradient dilutions. Incubate at room temperature for 15 minutes. Add the compound and serum mixture to the 96-well plate provided in the kit (100 μL/well) and activate at 37 degrees for 1 hour. Wash three times with wash buffer. Add the detection antibody (100 μL) provided by the kit and incubate at room temperature for 30 minutes. Wash three times with wash buffer. Add substrate (100 μL) and incubate at room temperature for 30 min. The absorbance was measured at 405nM with a microplate reader.
结论：本发明化合物对人血清旁路通路激活抑制活性明显。Conclusion: The compound of the present invention has obvious inhibitory activity on the activation of human serum bypass pathway.
实验测试方法2：补体人Factor B蛋白结合测试(TR-FRET法)Experimental test method 2: Complement human Factor B protein binding test (TR-FRET method)
实验目的：Purpose:
利用TR-FRET方法，对待测化合物针对人补体Factor B蛋白的结合活性的测定。The TR-FRET method was used to determine the binding activity of the test compound against human complement Factor B protein.
实验方案：Experimental program:
将药物加入磷酸盐缓冲液PBS(pH 7.4)中，从10μM开始，4倍稀释，10个浓度。生物素化的Factor B (25nM)在不存在或存在不同浓度的测试化合物的情况下，添加Cy5标记的探针(75nM)和铕螯合物标记的链霉亲和素(Perkin Elmer#AD0060；0.225nM)后，在室温下孵育2小时。使用330nm作为激发波长和665nm作为发射波长，测量时间分辨荧光能量转移(TR-FRET)数据。The drugs were added to phosphate buffered saline PBS (pH 7.4) starting from 10 μM and diluted 4 times to 10 concentrations. Biotinylated Factor B (25 nM) after the addition of Cy5-labeled probe (75 nM) and europium chelate-labeled streptavidin (Perkin Elmer #AD0060; 0.225 nM) in the absence or presence of different concentrations of test compound. Incubate at room temperature for 2 hours. Time-resolved fluorescence energy transfer (TR-FRET) data were measured using 330 nm as the excitation wavelength and 665 nm as the emission wavelength.
结论：本发明化合物对人补体Factor B蛋白具有显著的结合活性。Conclusion: The compound of the present invention has significant binding activity to human complement Factor B protein.
实验测试方法3：大鼠药代动力学研究Experimental Test Method 3: Rat Pharmacokinetic Study
实验目的：Purpose:
以雄性SD大鼠为受试动物，应用LC/MS/MS法测定大鼠口服灌胃给予本发明的化合物后不同时刻血浆中的药物浓度。研究本发明的化合物在大鼠体内的药代动力学行为，评价其药代动力学特征。Male SD rats were used as test animals, and the LC/MS/MS method was used to determine the drug concentration in the plasma of the rats at different times after oral administration of the compound of the present invention. Study the pharmacokinetic behavior of the compound of the present invention in rats and evaluate its pharmacokinetic characteristics.
试验方案：Test plan:
健康雄性大鼠200-300g，每组2只。Healthy male rats weighing 200-300g, 2 rats per group.
将本发明化合物，用0.5％MC(4000cP)/0.5％Tween 80的水溶液配制成1mg/mL的澄清溶液。大鼠禁食一夜后给药，剂量：10mg/kg，给药方式：口服灌胃。于给药前及给药后0.25、0.5、1、2、4、7、24小时采血，置于肝素化抗凝试管中，7000rpm(5204g)、4℃下离心，分离血浆，于-80℃保存。给药后4小时进食。用LC/MS/MS法测定口服给药后大鼠血浆中的待测化合物含量。血浆样品经沉淀蛋白预处理后进行分析。The compound of the present invention was prepared into a clear solution of 1 mg/mL with an aqueous solution of 0.5% MC (4000cP)/0.5% Tween 80. Rats were fasted overnight before administration, dose: 10 mg/kg, administration method: oral gavage. Collect blood before and 0.25, 0.5, 1, 2, 4, 7, and 24 hours after administration, place it in a heparinized anticoagulant test tube, centrifuge at 7000 rpm (5204g), 4°C, separate plasma, and store at -80°C save. Eat 4 hours after dosing. The LC/MS/MS method was used to determine the content of the test compound in rat plasma after oral administration. Plasma samples were analyzed after pretreatment with precipitated proteins.
结论：本发明化合物具有较好的口服暴露量和较长的半衰期，药代动力学性质优良。Conclusion: The compound of the present invention has good oral exposure, long half-life, and excellent pharmacokinetic properties.
实验测试方法4：LPS诱导补体激活小鼠体内PD模型Experimental test method 4: LPS-induced complement activation in vivo mouse PD model
实验目的：Purpose:
考察本发明实施例化合物对LPS刺激诱导小鼠补体激活的抑制作用。The inhibitory effect of the compounds of the present invention on complement activation in mice induced by LPS stimulation was examined.
实验动物：Experimental animals:
雌性C57BL/6J小鼠，7-9周龄，体重17-23克；供应商：上海西普尔-必凯实验动物有限公司。Female C57BL/6J mice, 7-9 weeks old, weighing 17-23 grams; supplier: Shanghai Sipur-Bika Experimental Animal Co., Ltd.
实验过程：experiment procedure:
在给药前4小时，将鼠伤寒沙门氏菌(Sigma)中的100μg脂多糖(LPS)溶解在100μL无菌PBS(磷酸盐缓冲液pH 7.2-7.4)中通过腹腔内注射诱导小鼠补体激活。正常小鼠组(阴性对照)：动物接受腹膜内注射100μL无菌PBS，并通过灌饲法(PO)单独给药溶媒。模型组(阳性对照)：动物接受腹腔内LPS和PO给药溶媒(20％PEG400/10％solutol/70％水)。药物组：给药化合物(溶媒：20％PEG400/10％solutol/70％水，给药体积：5mL/kg，剂量：10mg/kg)后4小时，进行样品采集。Complement activation was induced in mice by intraperitoneal injection of 100 μg lipopolysaccharide (LPS) from Salmonella typhimurium (Sigma) dissolved in 100 μL sterile PBS (phosphate buffer pH 7.2-7.4) 4 hours before administration. Normal mouse group (negative control): animals received an intraperitoneal injection of 100 μL of sterile PBS, and vehicle alone was administered by gavage (PO). Model group (positive control): animals received intraperitoneal LPS and PO administration of vehicle (20% PEG400/10% solutol/70% water). Drug group: Samples were collected 4 hours after compound administration (vehicle: 20% PEG400/10% solution/70% water, administration volume: 5 mL/kg, dose: 10 mg/kg).
样品采集：从眼眶静脉丛采集血液样本0.3mL。所有血样均加入规格为1.5mL的商品化EDTA-K2抗凝管中(供应商为江苏康健医疗用品有限公司)。血样采集后，在半小时内，于4℃、3000g离心10分钟吸取上清血浆，迅速至于干冰中，于-80℃冰箱保存，用于Western blot分析补体激活后下游C3d蛋白水平。Sample collection: 0.3 mL of blood sample was collected from the orbital venous plexus. All blood samples were added into commercial EDTA-K2 anticoagulant tubes with a specification of 1.5 mL (supplier is Jiangsu Kangjian Medical Products Co., Ltd.). After blood samples are collected, within half an hour, centrifuge at 4°C and 3000g for 10 minutes to aspirate the supernatant plasma, quickly transfer it to dry ice, and store it in a -80°C refrigerator for Western blot analysis of downstream C3d protein levels after complement activation.
样品分析：小鼠血浆(5μL)+Lysis buffer(裂解液，27.5μL)+Loading buffer(上样缓冲液，12.5μL)+Reducing buffer(还原缓冲液，5μL)混匀100℃孵育15min，上样量为5μL/孔，即每孔血浆上样量为0.5μL。Sample analysis: Mouse plasma (5 μL) + Lysis buffer (lysis buffer, 27.5 μL) + Loading buffer (loading buffer, 12.5 μL) + Reducing buffer (reducing buffer, 5 μL), mix well, incubate at 100°C for 15 minutes, and load the sample The volume is 5 μL/well, that is, the plasma loading volume per well is 0.5 μL.
实验结论：与正常组和模型组相比，本发明化合物能够或者能够显著抑制LPS刺激的补体激活。Experimental conclusion: Compared with the normal group and model group, the compound of the present invention can or can significantly inhibit complement activation stimulated by LPS.
技术效果Technical effect
本发明化合物对人血清旁路通路激活抑制活性明显，且对人补体Factor B蛋白的结合活性也较显著； 在各种属血浆中均具有中等的血浆蛋白结合率，预示在各种属的血浆中，本发明化合物的游离态药物浓度比例适中；具有良好的药代动力学性质(例如AUC、或F)，具有较好的肝微粒体代谢稳定性；化合物具有较好的渗透性；能够显著抑制LPS刺激的补体激活，可以发展成为新的补体系统Factor B小分子抑制剂。The compound of the present invention has obvious inhibitory activity on the activation of the human serum bypass pathway, and its binding activity to human complement Factor B protein is also significant; It has a moderate plasma protein binding rate in the plasma of various genera, indicating that in the plasma of various genera, the free drug concentration ratio of the compound of the present invention is moderate; it has good pharmacokinetic properties (such as AUC, or F), It has good metabolic stability of liver microsomes; the compound has good permeability; it can significantly inhibit complement activation stimulated by LPS, and can be developed into a new small molecule inhibitor of Factor B of the complement system.
相关定义Related definitions
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning. Where a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, as well as their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to the present invention. within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise stated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise stated, the term "cis-trans isomers" or "geometric isomers" refers to the inability of the double bonds or single bonds of the carbon atoms in the ring to rotate freely.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise stated, the term "diastereomer" refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise stated, "(+)" means right-handed, "(-)" means left-handed, and "(±)" means racemic.
除非另有说明，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，用直形实线键和直形虚线键表示立体中心的相对构型，用波浪线表示楔形实线键或楔形虚线键或用波浪线表示直形实线键或直形虚线键 Unless otherwise stated, use wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center, using straight solid line keys and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line Represents wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key or straight dotted key
除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平 衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。互变异构体以及它们的混合物，均包括在本发明的范围之内。Unless otherwise stated, the term "tautomer" or "tautomeric form" refers to the dynamic equilibrium state of isomers with different functional groups at room temperature. balance and can quickly transform into each other. If tautomers are possible (eg in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enol isomerization. Amine isomerization. Valence tautomers involve interconversions through the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the tautomerization between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Tautomers and mixtures thereof are included within the scope of the present invention.
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise stated, the terms "enriched in an isomer," "enantiomerically enriched," "enriched in an enantiomer," or "enantiomerically enriched" refer to one of the isomers or enantiomers. The content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。Unless otherwise stated, the term "isomeric excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). For another example, deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。The terms "optionally" or "optionally" mean that the subsequently described event or condition may, but need not, occur, and that the description includes instances in which the stated event or condition occurs and instances in which it does not. .
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e. =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。例如，如果一个基团被0个R所取代，则表示该基团未被取代。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. Thus, for example, if a group is substituted by 0-2 R, then said group may optionally be substituted by up to two R's, with independent options for R in each case. For example, if a group is substituted with 0 R's, it means that the group is unsubstituted. Furthermore, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。When the listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom thereof. For example, a pyridyl group as a substituent can be bonded through any one of the pyridine rings. The carbon atom is attached to the substituted group.
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键直形虚线键或波浪线表示。例如-OCH3中的直形实线键表示通过该基团中的氧原子与其他基团相连；中的直形虚线键表示通过该基团中的氮原子的 两端与其他基团相连；中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括 这4种连接方式，即使-N-上画出了H原子，但是仍包括这种连接方式的基团，只是在连接1个化学键时，该位点的H会对应减少1个变成相应的一价哌啶基。Unless otherwise specified, when a certain group has one or more attachable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the connection mode of the chemical bond is non-positioned and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will be reduced correspondingly with the number of connected chemical bonds and become the corresponding valence. group. The chemical bond connecting the site to other groups can be a straight solid line bond straight dashed key or wavy lines express. For example, the straight solid line bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in represents the bond through the nitrogen atom in the group Both ends are connected to other groups; The wavy lines in indicate that the phenyl group is connected to other groups through the 1 and 2 carbon atoms in the phenyl group; Indicates that any connectable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if H atoms are drawn on -N-, still includes For groups with this type of connection, only when a chemical bond is connected, the H at that position will be reduced by one and become the corresponding monovalent piperidinyl group.
当变量(例如R)取代在多环体系的其中一个环上时，除非另有规定，所述变量(例如R)指定为在该环上取代，而不能取代在多环体系的其它环上，例如表示环A与环B并环且取代基R1为环A的取代基、取代基R2为环B的取代基，表示螺环体系中的五元环被n个R所取代。When a variable (such as R) is substituted on one of the rings of a polycyclic system, unless otherwise specified, the variable (such as R) is designated as being substituted on that ring and cannot be substituted on other rings of the polycyclic system, For example Indicates that ring A and ring B are combined rings, and the substituent R 1 is a substituent of ring A, and the substituent R 2 is a substituent of ring B, Indicates that the five-membered ring in the spiro ring system is replaced by n R's.
除非另有规定，术语“C1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C1-6烷基包括C1-2和C2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。Unless otherwise specified, the term "C 1-3 alkyl" is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-6 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) . Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n - propyl and isopropyl), and the like.
除非另有规定，术语“C1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氧基包括C1-2、C2-3、C3和C2烷氧基等。C1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。Unless otherwise specified, the term "C 1-3 alkoxy" means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups, etc. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
除非另有规定，术语“C1-6烷硫基”表示通过硫原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C1-6烷硫基包括C1-4、C1-3、C1-2、C2-6、C2-4、C6、C5、C4、C3和C2烷硫基等。C1-6烷硫基的实例包括但不限于-SCH3、-SCH2CH3、-SCH2CH2CH3、-SCH2(CH3)2等等。Unless otherwise specified, the term "C 1-6 alkylthio" means those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through a sulfur atom. The C 1-6 alkylthio group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkane Sulfur group etc. Examples of C 1-6 alkylthio groups include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 , and the like.
除非另有规定，术语“C1-3烷硫基”表示通过硫原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷硫基包括C1-3、C1-2和C3烷硫基等。C1-3烷硫基的实例包括但不限于-SCH3、-SCH2CH3、-SCH2CH2CH3、-SCH2(CH3)2等。Unless otherwise specified, the term "C 1-3 alkylthio" means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through a sulfur atom. The C 1-3 alkylthio group includes C 1-3 , C 1-2 and C 3 alkylthio groups, etc. Examples of C 1-3 alkylthio groups include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 , and the like.
除非另有规定，“C2-6烯基”用于表示直链或支链的包含至少一个碳-碳双键的由2至6个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。所述C2-6烯基包括C2-4、C2-3、C4、C3和C2烯基等；其可以是一价、二价或者多价。C2-6烯基的实例包括但不限于乙烯基、丙烯基、丁烯基、戊烯基、己烯基、丁间二烯基、戊间二烯基、己间二烯基等。Unless otherwise specified, "C 2-6 alkenyl" is used to mean a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond. Can be located anywhere on the group. The C 2-6 alkenyl group includes C 2-4 , C 2-3 , C 4 , C 3 and C 2 alkenyl groups, etc.; it can be monovalent, divalent or multivalent. Examples of C 2-6 alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylene, hexadienyl, and the like.
除非另有规定，“C2-3烯基”用于表示直链或支链的包含至少一个碳-碳双键的由2至3个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。所述C2-3烯基包括C3和C2烯基；所述C2-3烯基可以是一价、二价或者多价。C2-3烯基的实例包括但不限于乙烯基、丙烯基等。Unless otherwise specified, "C 2-3 alkenyl" is used to mean a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, carbon-carbon double bond Can be located anywhere on the group. The C 2-3 alkenyl group includes C 3 and C 2 alkenyl groups; the C 2-3 alkenyl group can be monovalent, divalent or multivalent. Examples of C 2-3 alkenyl groups include, but are not limited to, vinyl, propenyl, and the like.
除非另有规定，“C2-6炔基”用于表示直链或支链的包含至少一个碳-碳三键的由2至6个碳原子组成的 碳氢基团，碳-碳三键可以位于该基团的任何位置上。所述C2-6炔基包括C2-4、C2-3、C4、C3和C2炔基等。其可以是一价、二价或者多价。C2-6炔基的实例包括但不限于乙炔基、丙炔基、丁炔基、戊炔基等。Unless otherwise specified, "C 2-6 alkynyl" is used to mean a straight or branched chain of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond. For a hydrocarbon group, the carbon-carbon triple bond can be located at any position on the group. The C 2-6 alkynyl group includes C 2-4 , C 2-3 , C 4 , C 3 and C 2 alkynyl groups, etc. It can be monovalent, bivalent or polyvalent. Examples of C 2-6 alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
除非另有规定，“C2-3炔基”用于表示直链或支链的包含至少一个碳-碳三键的由2至3个碳原子组成的碳氢基团，碳-碳三键可以位于该基团的任何位置上。其可以是一价、二价或者多价。所述C2-3炔基包括C3和C2炔基。C2-3炔基的实例包括但不限于乙炔基、丙炔基等。Unless otherwise specified, "C 2-3 alkynyl" is used to mean a straight-chain or branched hydrocarbon group composed of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond. Can be located anywhere on the group. It can be monovalent, bivalent or polyvalent. The C 2-3 alkynyl group includes C 3 and C 2 alkynyl groups. Examples of C 2-3 alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.
除非另有规定，“C3-6环烷基”表示由3至6个碳原子组成的饱和单环碳氢基团，所述C3-6环烷基包括C3-4、C3-5、C4-5、C4-6和C5-6环烷基等；其可以是一价、二价或者多价。C3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。Unless otherwise specified, "C 3-6 cycloalkyl" means a saturated monocyclic hydrocarbon group composed of 3 to 6 carbon atoms, and the C 3-6 cycloalkyl group includes C 3-4 , C 3- 5. C 4-5 , C 4-6 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or multivalent. Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
除非另有规定，“C3-4环烷基”表示由3至4个碳原子组成的饱和环状碳氢基团，其为单环体系，所述C3-4环烷基包括C3和C4环烷基等；其可以是一价、二价或者多价。C3-4环烷基的实例包括，但不限于，环丙基、环丁基。Unless otherwise specified, "C 3-4 cycloalkyl" means a saturated cyclic hydrocarbon group composed of 3 to 4 carbon atoms, which is a single ring system, and the C 3-4 cycloalkyl group includes C 3 and C 4 cycloalkyl, etc.; it can be monovalent, divalent or multivalent. Examples of C 3-4 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl.
除非另有规定，“3-6元杂环基”本身或者与其他术语联合分别表示由3至6个环原子组成的饱和或部分不饱和的单环环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。此外，就该“3-6元杂环基”而言，杂原子可以占据杂环基与分子其余部分的连接位置。所述3-6元杂环基包括4-6元、5-6元、4元、5元和6元杂环基等。3-6元杂环基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、等。Unless otherwise specified, "3-6-membered heterocyclyl" by itself or in combination with other terms respectively represents a saturated or partially unsaturated monocyclic cyclic group consisting of 3 to 6 ring atoms, where 1, 2, and 3 Or 4 ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S ( O) p , p is 1 or 2). Furthermore, in the case of the "3-6 membered heterocyclyl", the heteroatom may occupy the attachment position of the heterocyclyl to the rest of the molecule. The 3-6-membered heterocyclic groups include 4-6-membered, 5-6-membered, 4-membered, 5-membered and 6-membered heterocyclic groups, etc. Examples of 3-6 membered heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including Tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl) Aldinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), di Oxalkyl, dithialkyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, wait.
除非另有规定，“4-6元杂环烷基”是指完全饱和的4-6元杂环基。所述4-6元杂环烷基包括4-5元、5-6元、4元、5元和6元杂环烷基等。4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基。Unless otherwise specified, "4-6 membered heterocycloalkyl" refers to a fully saturated 4-6 membered heterocyclyl. The 4-6-membered heterocycloalkyl group includes 4-5-membered, 5-6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups, etc. Non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thibutanyl groups, and examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, and pyrrolidine. base, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, examples of 6-membered heterocycloalkyl include but are not limited to piperidinyl, tetrahydropyrazolyl Pyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithiane base, 1,4-dithianyl.
除非另有规定，Cn-n+m或Cn-Cn+m包括n至n+m个碳的任何一种具体情况，例如C1-12包括C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、和C12，也包括n至n+m中的任何一个范围，例如C1-12包括C1- 6、C1-6、C1-9、C3-6、C3-9、C3-12、C6-9、C6-12、和C9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。Unless otherwise specified, C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , also include any range from n to n+m, for example, C1-12 includes C1-6 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; similarly, n yuan to n The +m member indicates that the number of atoms in the ring is n to n+m. For example, a 3-12 membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, and a 9-membered ring. , 10-membered ring, 11-membered ring, and 12-membered ring, also including any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, etc.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝 对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。The structure of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute structure of the compound, For configuration, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal. The light source is CuKα radiation. The scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
本发明所使用的溶剂可经市售获得。化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。The solvent used in the present invention is commercially available. Compounds are named according to conventional naming principles in the field or use For software naming, commercially available compounds adopt supplier catalog names.
附图说明Description of drawings
图1：LPS诱导补体激活小鼠体内PD模型实验结果。Figure 1: Experimental results of LPS-induced complement activation in mouse PD model.
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention is described in detail below through examples, which do not mean any adverse limitations to the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. will be obvious.
参考例1：中间体N-c合成
Reference Example 1: Synthesis of Intermediate Nc
第一步first step
在15℃，向化合物N-a(0.5g,3.10mmol)的四氢呋喃(5mL)溶液中加入二碳酸二叔丁酯(812.33mg,3.72mmol)和N,N-二异丙基乙基胺(37.89mg,310.17μmol)。反应液在15℃下搅拌1小时。反应液加入水(15mL)中，继续搅拌5分钟。分液，水相用乙酸乙酯(20mL)萃取3次。合并的有机层用饱和食盐水(20mL)洗涤2次，无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝0:1至1:10)，得到化合物N-b。1H NMR(400MHz,CDCl3)δppm 7.54-7.48(m,1H),6.90-6.84(m,1H),6.77-6.70(m,1H),6.50-6.43(m,1H),3.90-3.77(m,3H),2.70-2.55(m,3H),1.66-1.61(m,9H)；LC-MS:m/z＝206.1[M-56+H]+。At 15°C, to a solution of compound Na (0.5g, 3.10mmol) in tetrahydrofuran (5mL) were added di-tert-butyl dicarbonate (812.33mg, 3.72mmol) and N,N-diisopropylethylamine (37.89mg ,310.17μmol). The reaction solution was stirred at 15°C for 1 hour. The reaction solution was added to water (15 mL), and stirring was continued for 5 minutes. The liquids were separated, and the aqueous phase was extracted three times with ethyl acetate (20 mL). The combined organic layers were washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:10) to obtain compound Nb. 1 H NMR (400MHz, CDCl 3 ) δppm 7.54-7.48(m,1H),6.90-6.84(m,1H),6.77-6.70(m,1H),6.50-6.43(m,1H),3.90-3.77( m,3H), 2.70-2.55(m,3H), 1.66-1.61(m,9H); LC-MS: m/z=206.1[M-56+H] + .
第二步Step 2
在15℃下，向氮气保护的N-甲基-N-甲酰基苯胺(459.93mg,3.40mmol)的二氯甲烷(2.7mL)溶液中缓慢滴加草酰氯(431.90mg,3.40mmol)。加完后，反应液在15℃下搅拌12小时后，逐滴加入到-14℃的化合物N-b(0.684g,2.62mmol)的二氯甲烷(2.8mL)溶液中。加完后反应液继续在-15℃下搅拌1.5小时。反应液倒入冰水(20mL)中，继续搅拌5分钟。水相用乙酸乙酯(20mL)萃取3次，合并的有机相用饱和食盐水(20mL)洗涤3次，无水硫酸钠干燥，过滤。滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝0:1至1:10)，得到化合物N-c。1H NMR(400MHz,DMSO-d6)δppm 10.61-10.41(m,1H),7.91-7.71(m,1H),7.38-7.21(m,1H),7.07-6.97(m,1H),3.97-3.93(m,3H),2.63-2.59(m,3H),1.60-1.58(m,9H)；LC-MS:m/z＝290.1[M+H]+。To a solution of N-methyl-N-formylanilide (459.93 mg, 3.40 mmol) in dichloromethane (2.7 mL) under nitrogen protection at 15°C, oxalyl chloride (431.90 mg, 3.40 mmol) was slowly added dropwise. After the addition was completed, the reaction solution was stirred at 15°C for 12 hours, and then added dropwise to a solution of compound Nb (0.684g, 2.62mmol) in dichloromethane (2.8mL) at -14°C. After the addition was completed, the reaction solution was continued to stir at -15°C for 1.5 hours. The reaction solution was poured into ice water (20 mL), and stirring was continued for 5 minutes. The aqueous phase was extracted three times with ethyl acetate (20 mL), and the combined organic phases were washed three times with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:10) to obtain compound Nc. 1 H NMR (400MHz, DMSO-d 6 ) δppm 10.61-10.41(m,1H),7.91-7.71(m,1H),7.38-7.21(m,1H),7.07-6.97(m,1H),3.97- 3.93(m,3H), 2.63-2.59(m,3H), 1.60-1.58(m,9H); LC-MS: m/z=290.1[M+H] + .
参考例2：中间体M-c的合成
Reference Example 2: Synthesis of Intermediate Mc
第一步first step
将苄胺(194.62g,1.82mol)缓慢加入到溶有醋酸(103.88mL,1.82mol)的水(850mL)中。将反应体系降温至0-10℃，然后缓慢分批加入1,3-丙酮二羧酸(265.36g,1.82mol)，反应液在0℃下反应0.5小时。将溶有化合物M-a(170g,908.15mmol)的二氧六环(850mL)溶液缓慢加入到反应体系中，将反应液缓慢恢复到室温，然后在45℃下反应12小时。反应液降至室温，然后加入乙酸乙酯萃取(500mL*2)，合并有机相，依次用饱和碳酸氢钠(500mL)和饱和氯化钠水溶液(500mL)洗涤，无水硫酸钠干燥后，滤液减压浓缩得到粗品。粗品在正庚烷和甲基叔丁基醚(1:1，500mL)混合溶剂中搅拌0.5小时，过滤并收集固体，得到化合物M-b。LC-MS:m/z＝317.1[M+H]+。Benzylamine (194.62g, 1.82mol) was slowly added to water (850mL) dissolved with acetic acid (103.88mL, 1.82mol). The reaction system was cooled to 0-10°C, and then 1,3-acetone dicarboxylic acid (265.36g, 1.82mol) was slowly added in batches, and the reaction solution was allowed to react at 0°C for 0.5 hours. A solution of compound Ma (170g, 908.15mmol) dissolved in dioxane (850mL) was slowly added to the reaction system, the reaction solution was slowly returned to room temperature, and then reacted at 45°C for 12 hours. The reaction solution was brought to room temperature, then ethyl acetate was added for extraction (500mL*2), the organic phases were combined, washed with saturated sodium bicarbonate (500mL) and saturated aqueous sodium chloride solution (500mL), and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain crude product. The crude product was stirred in a mixed solvent of n-heptane and methyl tert-butyl ether (1:1, 500 mL) for 0.5 hours, filtered and collected the solid to obtain compound Mb. LC-MS: m/z=317.1[M+H] + .
第二步Step 2
将化合物M-b(220g，696.20mmol)溶于乙腈(1700mL)中，然后升温到70℃下搅拌2小时，在搅拌下慢慢加入L-型二苯甲酰基酒石酸(200g,558.66mmol)，反应液继续在70℃下搅拌2小时，然后缓慢恢复到25℃，并搅拌12小时。过滤并收集固体，再用乙腈(400mL*2)洗涤滤饼。将过滤得到的固体加入到1000mL水中，搅拌下加入1M NaOH水溶液调节pH至8，然后加入乙酸乙酯萃取(2000mL*2)。合并有机相，并用饱和的食盐水(2000mL*2)洗涤，有机相用无水硫酸钠干燥，过滤后减压浓缩滤液得到化合物M-c(保留时间:2.175min，ee＝99.1％)。LC-MS:m/z＝317.1[M+H]+。SFC分析方法：色谱柱:Chiralpak AD 50×4.6mm I.D.,3μm，流动相:A:CO2，B:甲醇(0.05％二乙胺)，梯度B％：5％-40％。Compound Mb (220g, 696.20mmol) was dissolved in acetonitrile (1700mL), then the temperature was raised to 70°C and stirred for 2 hours. L-type dibenzoyl tartaric acid (200g, 558.66mmol) was slowly added under stirring, and the reaction solution Continue stirring at 70°C for 2 hours, then slowly return to 25°C and stir for 12 hours. Filter and collect the solid, then wash the filter cake with acetonitrile (400mL*2). Add the filtered solid to 1000 mL of water, add 1 M NaOH aqueous solution with stirring to adjust the pH to 8, and then add ethyl acetate for extraction (2000 mL*2). The organic phases were combined and washed with saturated brine (2000 mL*2). The organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain compound Mc (retention time: 2.175 min, ee=99.1%). LC-MS: m/z=317.1[M+H] + . SFC analysis method: Chromatographic column: Chiralpak AD 50×4.6mm ID, 3 μm, mobile phase: A: CO 2 , B: methanol (0.05% diethylamine), gradient B%: 5%-40%.
实施例1

Example 1

第一步first step
在0℃，向化合物M-c(30g,94.82mmol)的甲醇(150mL)和乙腈(150mL)的溶液中，分批加入硼氢化钠(3.95g,104.30mmol)，慢慢升至20℃，并在20℃下继续搅拌2小时。向反应液中缓慢滴加1M稀盐酸溶液淬灭反应，至无气泡产生。然后用饱和碳酸氢钠水溶液调节pH值至7～8，用乙酸乙酯(500mL*2)萃取，合并有机相用饱和食盐水(600mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。在25℃下，向粗品(27g,84.80mmol)的甲基叔丁基醚(135mL)溶液中缓慢加入盐酸/乙酸乙酯(4M,31.80mL)。在25℃下继续搅拌2小时。有固体析出，过滤，并收集固体。然后向得到的固体中加入水(200mL)和甲基叔丁基醚(300mL)，并用氢氧化钠水溶液(4M)调节pH至7到8，用甲基叔丁基醚(300mL)萃取，有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物1-1。LC-MS:m/z＝319.3[M+H]+。To a solution of compound Mc (30g, 94.82mmol) in methanol (150mL) and acetonitrile (150mL), sodium borohydride (3.95g, 104.30mmol) was added in batches at 0°C, slowly raised to 20°C, and Continue stirring at 20°C for 2 hours. Slowly add 1M dilute hydrochloric acid solution dropwise into the reaction solution to quench the reaction until no bubbles are generated. Then adjust the pH value to 7~8 with saturated aqueous sodium bicarbonate solution, extract with ethyl acetate (500mL*2), wash the combined organic phases with saturated brine (600mL*2), dry over anhydrous sodium sulfate, filter, and reduce the filtrate Concentrate under pressure to obtain crude product. To a solution of the crude product (27 g, 84.80 mmol) in methyl tert-butyl ether (135 mL) at 25°C was slowly added hydrochloric acid/ethyl acetate (4M, 31.80 mL). Stirring was continued at 25°C for 2 hours. If a solid precipitates, filter and collect the solid. Then, water (200 mL) and methyl tert-butyl ether (300 mL) were added to the obtained solid, and the pH was adjusted to 7 to 8 with aqueous sodium hydroxide solution (4M), and extracted with methyl tert-butyl ether (300 mL). The phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1-1. LC-MS: m/z=319.3[M+H] + .
第二步Step 2
将化合物1-1(10g,31.41mmol)和三乙胺(4.77g,47.11mmol)溶于溶剂二氯甲烷(100mL)中，降温至-20℃,缓慢滴加甲基磺酰氯(5.32g,46.48mmol)，反应液在-20℃下搅拌1小时。在-20℃下缓慢加入200mL水淬灭反应。然后加入二氯甲烷(250mL*2)萃取。合并有机相，并用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩。剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:10到1：3)，得到化合物1-2。LC-MS:m/z＝397.1[M+H]+。Dissolve compound 1-1 (10g, 31.41mmol) and triethylamine (4.77g, 47.11mmol) in the solvent dichloromethane (100mL), cool to -20°C, and slowly add methylsulfonyl chloride (5.32g, 46.48 mmol), the reaction solution was stirred at -20°C for 1 hour. Quench the reaction by slowly adding 200 mL of water at -20°C. Then add dichloromethane (250mL*2) for extraction. The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10 to 1:3) to obtain compound 1-2. LC-MS: m/z=397.1[M+H] + .
第三步third step
将乙硫醇(8.94g,143.82mmol)溶于四氢呋喃(60mL)溶液中，在氮气保护下氢化钠(6.14g,127.84mmol,50％纯度)。反应液在20℃下搅拌0.5小时。然后将溶有化合物1-2(6.4g,15.98mmol)的N,N-二甲基甲酰胺(60mL)溶液缓慢加入到反应液中。反应液在70℃下搅拌2小时。在0℃下向反应液中加入饱和氯化铵水溶液100mL淬灭反应，然后加入水100mL稀释。加入乙酸乙酯(500mL*2)萃取。合并有机相，并用饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:20到1：8)，得到化合物1-3。LC-MS:m/z＝363.1[M+H]+。Ethyl mercaptan (8.94g, 143.82mmol) was dissolved in tetrahydrofuran (60mL) solution, and sodium hydride (6.14g, 127.84mmol, 50% purity) was added under nitrogen protection. The reaction solution was stirred at 20°C for 0.5 hours. Then, a solution of compound 1-2 (6.4 g, 15.98 mmol) dissolved in N,N-dimethylformamide (60 mL) was slowly added to the reaction solution. The reaction solution was stirred at 70°C for 2 hours. Add 100 mL of saturated ammonium chloride aqueous solution to the reaction solution at 0°C to quench the reaction, and then add 100 mL of water to dilute. Add ethyl acetate (500mL*2) and extract. The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:8) to obtain compound 1-3. LC-MS: m/z=363.1[M+H] + .
第四步the fourth step
将化合物1-3(1.5g,4.14mmol)溶于叔丁醇(25mL)中，加入叔丁醇钾(1.39g,12.41mmol),反应液在70℃下搅拌0.5小时。将反应液冷却至20℃，反应液中加入水100mL稀释，加入乙酸乙酯(200mL*2)萃取。合并有机相，并用饱和食盐水(100mL*2)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩得到化合物1-4。LC-MS:m/z＝381.1[M+H]+。Compound 1-3 (1.5g, 4.14mmol) was dissolved in tert-butanol (25mL), potassium tert-butoxide (1.39g, 12.41mmol) was added, and the reaction solution was stirred at 70°C for 0.5 hours. Cool the reaction solution to 20°C, add 100 mL of water to the reaction solution to dilute, and add ethyl acetate (200 mL*2) for extraction. Combine the organic phases, wash with saturated brine (100 mL*2), dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure to obtain compound 1-4. LC-MS: m/z=381.1[M+H] + .
第五步the fifth step
将化合物1-4(1.5g,3.94mmol)溶于甲醇(30mL)中，加入N,N-二甲基甲酰胺二甲基缩醛(1.41g,11.83mmol),反应液在70℃下搅拌12小时。将反应液冷却至20℃，反应液中加入水100mL稀释，加入乙酸 乙酯(200mL*2)萃取。合并有机相，并用饱和食盐水(100mL*2)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩得到化合物1-5。LC-MS:m/z＝396.3[M+H]+。Compound 1-4 (1.5g, 3.94mmol) was dissolved in methanol (30mL), N,N-dimethylformamide dimethyl acetal (1.41g, 11.83mmol) was added, and the reaction solution was stirred at 70°C. 12 hours. Cool the reaction solution to 20°C, add 100 mL of water to the reaction solution to dilute, and add acetic acid Extract with ethyl ester (200mL*2). Combine the organic phases, wash with saturated brine (100 mL*2), dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure to obtain compound 1-5. LC-MS: m/z=396.3[M+H] + .
第六步Step 6
将化合物1-5(1.0g,2.53mmol)溶于甲醇(30mL)中，在氮气保护下依次加入浓盐酸(614.51mg,5.06mmol,37％纯度)和湿钯碳(3g,10％纯度)，氢气置换3次，在50℃，氢气氛围下，搅拌2小时。将反应液冷却至20℃，过滤，滤液浓缩得到化合物1-6。LC-MS:m/z＝306.1[M+H]+。Compound 1-5 (1.0g, 2.53mmol) was dissolved in methanol (30mL), and concentrated hydrochloric acid (614.51mg, 5.06mmol, 37% purity) and wet palladium on carbon (3g, 10% purity) were added in sequence under nitrogen protection. , replaced with hydrogen three times, and stirred for 2 hours at 50°C in a hydrogen atmosphere. The reaction solution was cooled to 20°C, filtered, and the filtrate was concentrated to obtain compound 1-6. LC-MS: m/z=306.1[M+H] + .
第七步Step 7
将化合物1-6(400mg,1.31mmol)和化合物N-c(341.01mg,1.18mmol)溶于1，4-二氧六环(10mL)中，依次加入吡啶(124.31mg,1.57mmol)和三氟化硼乙醚(223.05mg,1.57mmol)。然后加入聚甲基硅氧烷(787.43mg,13.10mmol)，反应液在氮气保护下于100℃下搅拌12小时。将反应液冷却至20℃，加入水100mL稀释。加入乙酸乙酯(200mL*2)萃取。合并有机相，并用饱和食盐水(200mL*2)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩。剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:20到1：5)，得到化合物1-7。LC-MS:m/z＝579.3[M+H]+。Compound 1-6 (400 mg, 1.31 mmol) and compound Nc (341.01 mg, 1.18 mmol) were dissolved in 1,4-dioxane (10 mL), and pyridine (124.31 mg, 1.57 mmol) and trifluoride were added successively. Boron ether (223.05mg, 1.57mmol). Then polymethylsiloxane (787.43 mg, 13.10 mmol) was added, and the reaction solution was stirred at 100°C for 12 hours under nitrogen protection. The reaction solution was cooled to 20°C, and 100 mL of water was added to dilute it. Add ethyl acetate (200mL*2) and extract. Combine the organic phases, wash with saturated brine (200 mL*2), dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:5) to obtain compound 1-7. LC-MS: m/z=579.3[M+H] + .
第八步Step 8
向化合物1-7(450mg,777.52μmol)的四氢呋喃(5mL)和甲醇(5mL)溶液中加入氢氧化锂水溶液(4M,1.94mL)，在50℃下搅拌2小时。将反应液浓缩后得到的剩余物用醋酸调节pH到7，然后减压浓缩，得到的残留物用高效液相色谱法纯化(色谱柱:Phenomenex C18 150×40mm×15μm；流动相：A：水(0.225％甲酸)，B：乙腈，方法：B：16％-46％)得到化合物1A的甲酸盐和化合物1B的甲酸盐。To a solution of compound 1-7 (450 mg, 777.52 μmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added aqueous lithium hydroxide solution (4 M, 1.94 mL), and the mixture was stirred at 50° C. for 2 hours. The residue obtained after concentrating the reaction solution was adjusted to pH 7 with acetic acid, and then concentrated under reduced pressure. The residue obtained was purified by high performance liquid chromatography (chromatographic column: Phenomenex C18 150×40mm×15μm; mobile phase: A: water (0.225% formic acid), B: acetonitrile, method: B: 16%-46%) to obtain the formate salt of compound 1A and the formate salt of compound 1B.
化合物1A的甲酸盐表征：(保留时间:1.692min，HPLC分析方法：色谱柱:Kinetex EVO C18 50×4.6mm,5μm，流动相:A水(0.0375％三氟乙酸)，B:乙腈(0.01875％三氟乙酸)，梯度B％：10％-80％)，1H NMR(400MHz,DMSO-d6)δppm 10.83(br s,1H),8.18(s,1H),7.98(d,J＝8.4Hz,2H),7.74(d,J＝8.4Hz,2H),7.27(t,J＝2.8Hz,1H),6.67(s,1H),6.47(d,J＝2.6Hz,1H),3.78(br d,J＝12.2Hz,1H),3.73(s,3H),3.22-3.11(m,3H),2.59(q,J＝7.4Hz,2H),2.43(s,3H),2.19-1.94(m,5H),1.85(br s,1H),1.64(br d,J＝7.3Hz,1H),1.55-1.47(m,1H),1.20(t,J＝7.4Hz,3H)；LC-MS:m/z＝465.2[M+H]+。Characterization of formate salt of compound 1A: (retention time: 1.692min, HPLC analysis method: chromatographic column: Kinetex EVO C18 50×4.6mm, 5μm, mobile phase: A water (0.0375% trifluoroacetic acid), B: acetonitrile (0.01875 % trifluoroacetic acid), gradient B%: 10%-80%), 1 H NMR (400MHz, DMSO-d 6 ) δppm 10.83 (br s, 1H), 8.18 (s, 1H), 7.98 (d, J＝ 8.4Hz,2H),7.74(d,J＝8.4Hz,2H),7.27(t,J＝2.8Hz,1H),6.67(s,1H),6.47(d,J＝2.6Hz,1H),3.78 (br d,J＝12.2Hz,1H),3.73(s,3H),3.22-3.11(m,3H),2.59(q,J＝7.4Hz,2H),2.43(s,3H),2.19-1.94 (m,5H),1.85(br s,1H),1.64(br d,J＝7.3Hz,1H),1.55-1.47(m,1H),1.20(t,J＝7.4Hz,3H); LC- MS: m/z=465.2[M+H] + .
化合物1B的甲酸盐表征：(保留时间:1.779min，HPLC分析方法：色谱柱:Kinetex EVO C18 50×4.6mm,5μm，流动相:A水(0.0375％三氟乙酸)，B:乙腈(0.01875％三氟乙酸)，梯度B％：10％-80％)，1H NMR(400MHz,DMSO-d6)δppm 10.87(br s,1H),8.19(s,1H),7.99(d,J＝8.4Hz,2H),7.79(d,J＝8.4Hz,2H),7.28(t,J＝2.8Hz,1H),6.68(s,1H),6.51(d,J＝2.6Hz,1H),3.79(br d,J＝12.2Hz,1H),3.76(s,3H),3.21-3.19(m,3H),2.61(q,J＝7.4Hz,2H),2.47(s,3H),2.19-1.95(m,5H),1.88(br s,1H),1.66(br d,J＝7.3Hz,1H),1.56-1.43(m,1H),1.22(t,J＝7.4Hz,3H)；LC-MS:m/z＝465.2[M+H]+。Characterization of formate salt of compound 1B: (retention time: 1.779min, HPLC analysis method: chromatographic column: Kinetex EVO C18 50×4.6mm, 5μm, mobile phase: A water (0.0375% trifluoroacetic acid), B: acetonitrile (0.01875 % trifluoroacetic acid), gradient B%: 10%-80%), 1 H NMR (400MHz, DMSO-d 6 ) δppm 10.87 (br s, 1H), 8.19 (s, 1H), 7.99 (d, J＝ 8.4Hz,2H),7.79(d,J＝8.4Hz,2H),7.28(t,J＝2.8Hz,1H),6.68(s,1H),6.51(d,J＝2.6Hz,1H),3.79 (br d,J＝12.2Hz,1H),3.76(s,3H),3.21-3.19(m,3H),2.61(q,J＝7.4Hz,2H),2.47(s,3H),2.19-1.95 (m,5H),1.88(br s,1H),1.66(br d,J＝7.3Hz,1H),1.56-1.43(m,1H),1.22(t,J＝7.4Hz,3H); LC- MS: m/z=465.2[M+H] + .
化合物1A相对1B在手性色谱柱中的保留时间短，化合物1B相对1A在手性色谱柱中的保留时间长。Compound 1A has a shorter retention time in the chiral chromatography column than 1B, and compound 1B has a longer retention time in the chiral chromatography column than 1A.
实施例2
Example 2
第一步first step
在室温下，向化合物1-2(2g,5.04mmol)的N,N-二甲基甲酰胺(30mL)溶液中加入甲硫醇钠(1.41g,20.18mmol)，升温至50℃下反应16小时。反应液冷却至室温，加入100mL水，然后用乙酸乙酯(50mL*3)萃取，饱和食盐水(60mL*2)洗涤，无水硫酸钠干燥，过滤，浓缩得到残留物。残留物硅胶柱层析法(乙酸乙酯:石油醚＝1:10)分离纯化得到化合物2-1。LC-MS:m/z＝349.3[M+H]+。At room temperature, add sodium methyl mercaptide (1.41g, 20.18mmol) to a solution of compound 1-2 (2g, 5.04mmol) in N,N-dimethylformamide (30mL), and raise the temperature to 50°C for reaction 16 Hour. The reaction solution was cooled to room temperature, 100 mL of water was added, and then extracted with ethyl acetate (50 mL*3), washed with saturated brine (60 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:10) to obtain compound 2-1. LC-MS: m/z=349.3[M+H] + .
第二步Step 2
在室温下，向化合物2-1(1.44g,4.13mmol)的叔丁醇(20mL)溶液中加入叔丁醇钾(1.39g,12.40mmol)，升温至50℃下反应4小时。反应液冷却至室温，加入20mL水稀释，然后用乙酸乙酯(50mL*3)萃取，合并有机相并用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物2-2。LC-MS:m/z＝367.3[M+H]+。Potassium tert-butoxide (1.39g, 12.40mmol) was added to a solution of compound 2-1 (1.44g, 4.13mmol) in tert-butanol (20mL) at room temperature, and the temperature was raised to 50°C and the reaction was carried out for 4 hours. The reaction solution was cooled to room temperature, diluted with 20 mL of water, and then extracted with ethyl acetate (50 mL*3). The organic phases were combined and washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 2- 2. LC-MS: m/z=367.3[M+H] + .
第三步third step
向化合物2-2(1g,2.73mmol)的甲醇溶液(20mL)中加入N,N-二甲基甲酰胺二甲基缩醛(975.35mg,8.19mmol),升温至50℃反应16小时。将反应液冷却至室温，减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:10)，得到化合物2-3。LC-MS:m/z＝382.3[M+H]+。N,N-dimethylformamide dimethyl acetal (975.35 mg, 8.19 mmol) was added to the methanol solution (20 mL) of compound 2-2 (1 g, 2.73 mmol), and the temperature was raised to 50°C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:10) to obtain compound 2-3. LC-MS: m/z=382.3[M+H] + .
第四步the fourth step
在氮气的保护下，向化合物2-3(0.8g,2.10mmol)的甲醇(10mL)溶液中加入湿钯碳(1g,10％纯度)和浓盐酸(254.84mg,2.10mmol,37％纯度)，用氢气置换三次，并在氢气氛围，60℃下反应6小时。将反应液冷却至室温后过滤，滤液减压浓缩得到化合物2-4。LC-MS:m/z＝292.4[M+H]+。Under the protection of nitrogen, to a solution of compound 2-3 (0.8g, 2.10mmol) in methanol (10mL) were added wet palladium on carbon (1g, 10% purity) and concentrated hydrochloric acid (254.84mg, 2.10mmol, 37% purity) , replaced with hydrogen three times, and reacted in a hydrogen atmosphere at 60°C for 6 hours. The reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 2-4. LC-MS: m/z=292.4[M+H] + .
第五步the fifth step
室温下，向化合物2-4(300mg,1.03mmol)的1,4-二氧六环溶液(3mL)中加入N-c(357.43mg,1.24mmol)，吡啶(97.72mg,1.24mmol),三氟化硼乙醚(175.34mg,1.24mmol)和聚甲基硅氧烷(619.03mg,10.29mmol)，升温至100℃，反应16小时。冷却至室温，将反应液过滤，并用乙酸乙酯洗涤滤饼，滤液依次用柠檬酸洗涤(1mL*2)，饱和碳酸氢钠洗涤(1mL*2)和饱和食盐水洗涤(1mL*2)，无水硫酸钠干燥，过滤，浓缩得到残留物。残留物用硅胶柱层析法(乙酸乙酯:石油醚＝1：10)分离纯化得到化合物2-5.LC-MS:m/z＝565.4[M+H]+。 At room temperature, Nc (357.43 mg, 1.24 mmol), pyridine (97.72 mg, 1.24 mmol), and trifluoride were added to the 1,4-dioxane solution (3 mL) of compound 2-4 (300 mg, 1.03 mmol). Boron ether (175.34 mg, 1.24 mmol) and polymethylsiloxane (619.03 mg, 10.29 mmol) were heated to 100°C and reacted for 16 hours. Cool to room temperature, filter the reaction solution, and wash the filter cake with ethyl acetate. The filtrate is washed with citric acid (1mL*2), saturated sodium bicarbonate (1mL*2), and saturated brine (1mL*2). Dry over anhydrous sodium sulfate, filter, and concentrate to obtain a residue. The residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:10) to obtain compound 2-5. LC-MS: m/z = 565.4 [M+H] + .
第六步Step 6
向化合物2-5(0.37g,655.18μmol)的甲醇(3mL)和四氢呋喃(3mL)溶液中加入氢氧化锂水溶液(4M,3mL)，在50℃下搅拌3小时。反应完全后，冷却至室温，加入醋酸调节pH至7左右，浓缩得到残留物。残留物用高效液相色谱法纯化(色谱柱:Phenomenex luna C18 250×80mm，10μm；流动相:A:水(0.225％甲酸)；B:乙腈；方法B:30％-60％)分离纯化得到化合物2A的甲酸盐和化合物2B的甲酸盐。To a solution of compound 2-5 (0.37 g, 655.18 μmol) in methanol (3 mL) and tetrahydrofuran (3 mL) was added aqueous lithium hydroxide solution (4 M, 3 mL), and the mixture was stirred at 50° C. for 3 hours. After the reaction is complete, cool to room temperature, add acetic acid to adjust the pH to about 7, and concentrate to obtain a residue. The residue was purified by high performance liquid chromatography (chromatographic column: Phenomenex luna C18 250×80mm, 10μm; mobile phase: A: water (0.225% formic acid); B: acetonitrile; method B: 30%-60%) to obtain The formate salt of compound 2A and the formate salt of compound 2B.
化合物2A的甲酸盐表征：(保留时间：1.612min，HPLC分析方法为：色谱柱:Kinetex EVO C18 50×4.6mm,5μm，流动相:A水(0.0375％三氟乙酸)，B:乙腈(0.01875％三氟乙酸)，梯度B％：10％-80％)，1H NMR(400MHz,DMSO-d6)δppm 10.89-10.71(m,1H),8.03-7.88(m,2H),7.80-7.67(m,2H),7.29-7.20(m,1H),6.69-6.58(m,1H),6.50-6.39(m,1H),3.82-3.74(m,1H),3.73-3.67(m,3H),3.18-3.11(m,2H),3.10-2.97(m,2H),2.43-2.37(m,3H),2.13-2.08(m,2H),2.08-2.06(m,3H),2.05-1.97(m,3H),1.92-1.76(m,1H),1.71-1.52(m,1H),1.52-1.37(m,1H)；LC-MS:m/z＝451.3[M+H]+。Characterization of formate of compound 2A: (retention time: 1.612min, HPLC analysis method is: chromatographic column: Kinetex EVO C18 50×4.6mm, 5μm, mobile phase: A water (0.0375% trifluoroacetic acid), B: acetonitrile ( 0.01875% trifluoroacetic acid), gradient B%: 10%-80%), 1 H NMR (400MHz, DMSO-d 6 ) δppm 10.89-10.71 (m, 1H), 8.03-7.88 (m, 2H), 7.80- 7.67(m,2H),7.29-7.20(m,1H),6.69-6.58(m,1H),6.50-6.39(m,1H),3.82-3.74(m,1H),3.73-3.67(m,3H ),3.18-3.11(m,2H),3.10-2.97(m,2H),2.43-2.37(m,3H),2.13-2.08(m,2H),2.08-2.06(m,3H),2.05-1.97 (m,3H), 1.92-1.76(m,1H), 1.71-1.52(m,1H), 1.52-1.37(m,1H); LC-MS: m/z=451.3[M+H] + .
化合物2B的甲酸盐表征：(保留时间：1.677min，HPLC分析方法为：色谱柱:Kinetex EVO C18 50×4.6mm,5μm，流动相:A水(0.0375％三氟乙酸)，B:乙腈(0.01875％三氟乙酸)，梯度B％：10％-80％)，1H NMR(400MHz,DMSO-d6)δppm 10.90-10.68(m,1H),8.15-8.07(m,1H),7.99-7.87(m,2H),7.79-7.67(m,2H),7.30-7.17(m,1H),6.72-6.59(m,1H),6.52-6.40(m,1H),3.78-3.70(m,1H),3.70-3.66(m,3H),3.22-3.13(m,3H),3.14-3.03(m,2H),2.41-2.36(m,3H),2.35-2.23(m,1H),2.18-2.08(m,2H),2.07(s,3H),2.02-1.89(m,2H),1.50-1.36(m,1H)；LC-MS:m/z＝451.3[M+H]+。Characterization of formate of compound 2B: (retention time: 1.677min, HPLC analysis method is: chromatographic column: Kinetex EVO C18 50×4.6mm, 5μm, mobile phase: A water (0.0375% trifluoroacetic acid), B: acetonitrile ( 0.01875% trifluoroacetic acid), gradient B%: 10%-80%), 1 H NMR (400MHz, DMSO-d 6 ) δppm 10.90-10.68 (m, 1H), 8.15-8.07 (m, 1H), 7.99- 7.87(m,2H),7.79-7.67(m,2H),7.30-7.17(m,1H),6.72-6.59(m,1H),6.52-6.40(m,1H),3.78-3.70(m,1H ),3.70-3.66(m,3H),3.22-3.13(m,3H),3.14-3.03(m,2H),2.41-2.36(m,3H),2.35-2.23(m,1H),2.18-2.08 (m,2H),2.07(s,3H),2.02-1.89(m,2H),1.50-1.36(m,1H); LC-MS: m/z=451.3[M+H] + .
化合物2A相对2B在手性色谱柱中的保留时间短，化合物2B相对2A在手性色谱柱中的保留时间长。Compound 2A has a shorter retention time in the chiral chromatography column than 2B, and compound 2B has a longer retention time in the chiral chromatography column than 2A.
实施例3
Example 3
第一步first step
在室温下，向化合物M-c(2g,6.32mmol)和(3-溴丙基)三苯溴化膦(3.81g,8.22mmol)的四氢呋喃(30mL)溶液中加入叔丁醇钾(1.84g,16.44mmol)，升温至50℃，氮气保护下反应16小时。反应结束后，反应液冷却至室温，加入100mL水，然后用乙酸乙酯(100mL)萃取，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到残留物。残留物硅胶柱层析法(乙酸乙酯:石油醚＝0：1到1:15)分离纯化得到化合物3-1。LC-MS:m/z＝341.2[M+H]+。To a solution of compound Mc (2g, 6.32mmol) and (3-bromopropyl)triphenylphosphine bromide (3.81g, 8.22mmol) in tetrahydrofuran (30mL) was added potassium tert-butoxide (1.84g, 16.44 mmol), raise the temperature to 50°C, and react for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, 100 mL of water was added, and then extracted with ethyl acetate (100 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:15) to obtain compound 3-1. LC-MS: m/z=341.2[M+H] + .
第二步Step 2
在室温下，向化合物3-1(1g,2.94mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入苯磺酰肼(1.52g,8.81mmol)，升温至100℃下反应3小时。反应液冷却至室温，加入50mL水稀释，然后用乙酸乙酯(50mL)萃取，合并有机相并用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到残留物硅胶柱层析法(乙酸乙酯:石油醚＝0：1到1:10)分离纯化得到化合物3-2。LC-MS:m/z＝343.4[M+H]+。At room temperature, add benzenesulfonyl hydrazide (1.52g, 8.81mmol) to a solution of compound 3-1 (1g, 2.94mmol) in N,N-dimethylformamide (10mL), and raise the temperature to 100°C to react 3 Hour. The reaction solution was cooled to room temperature, diluted by adding 50 mL of water, and then extracted with ethyl acetate (50 mL). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue by silica gel column chromatography. (Ethyl acetate:petroleum ether=0:1 to 1:10) separation and purification to obtain compound 3-2. LC-MS: m/z=343.4[M+H] + .
第三步third step
在室温下，向化合物3-2(0.62g,1.81mmol)的二甲基亚砜(5mL)溶液中加入碳酸钾(275.22mg,1.99mmol)和过氧化氢(307.89mg,2.72mmol，30％的水溶液)，升温至40℃下反应5小时。反应液冷却至室温，加入到20mL水中，有固体析出，过滤并收集固体，干燥后得到化合物3-3。LC-MS:m/z＝361.4[M+H]+。To a solution of compound 3-2 (0.62g, 1.81mmol) in dimethyl sulfoxide (5mL) was added potassium carbonate (275.22mg, 1.99mmol) and hydrogen peroxide (307.89mg, 2.72mmol, 30%) at room temperature. aqueous solution), raise the temperature to 40°C and react for 5 hours. The reaction solution was cooled to room temperature and added to 20 mL of water. A solid precipitated. The solid was filtered and collected. After drying, compound 3-3 was obtained. LC-MS: m/z=361.4[M+H] + .
第四步the fourth step
向化合物3-3(0.62g,1.72mmol)的甲醇(25mL)溶液中加入N,N-二甲基甲酰胺二甲基缩醛(614.83mg,5.16mmol)，升温至60℃反应16小时。反应液冷却至室温，加入30mL水稀释，然后用乙酸乙酯(30mL)萃取，合并有机相，并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物3-4。LC-MS:m/z＝376.4[M+H]+。N,N-dimethylformamide dimethyl acetal (614.83 mg, 5.16 mmol) was added to a solution of compound 3-3 (0.62 g, 1.72 mmol) in methanol (25 mL), and the temperature was raised to 60°C for 16 hours. The reaction solution was cooled to room temperature, diluted with 30 mL of water, and then extracted with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 3-4. LC-MS: m/z=376.4[M+H] + .
第五步the fifth step
在氮气的保护下，向化合物3-4(0.6g,1.60mmol)的甲醇(15mL)溶液中加入湿钯碳(0.6g,10％纯度)和浓盐酸(266.31μL,37％纯度)，用氢气置换三次，并在氢气氛围下，50℃下反应3小时。将反应液冷却至室温后过滤，滤液浓缩。剩余物中加入乙酸乙酯(15mL)稀释，饱和碳酸氢钠调节pH至9，加入乙酸乙酯(15mL)萃取，用饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物3-5。LC-MS:m/z＝286.4[M+H]+。Under the protection of nitrogen, add wet palladium on carbon (0.6g, 10% purity) and concentrated hydrochloric acid (266.31 μL, 37% purity) to a solution of compound 3-4 (0.6g, 1.60mmol) in methanol (15mL). Hydrogen was substituted three times, and the reaction was carried out at 50°C for 3 hours in a hydrogen atmosphere. The reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated. The residue was diluted with ethyl acetate (15 mL), adjusted to pH 9 with saturated sodium bicarbonate, extracted with ethyl acetate (15 mL), washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the compound. 3-5. LC-MS: m/z=286.4[M+H] + .
第六步Step 6
室温下，向化合物3-5(0.29g,1.02mmol)的1,4-二氧六环溶液(5mL)中加入化合物N-c(382.21mg,1.32mmol),吡啶(96.46mg,1.22mmol),三氟化硼乙醚(173.07mg,1.22mmol)和聚甲基硅氧烷(609.71mg,10.16mmol)，升温至90℃反应16小时。冷却至室温，加入20mL水稀释，然后用乙酸乙酯(20mL)萃取，合并有机相，并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到残留物。残留物用硅胶柱层析法(乙酸乙酯:石油醚＝1:20到1：5)分离纯化得到化合物3-6。LC-MS:m/z＝559.3[M+H]+。To a solution (5 mL) of compound 3-5 (0.29g, 1.02mmol) in 1,4-dioxane, compound Nc (382.21mg, 1.32mmol), pyridine (96.46mg, 1.22mmol), and trifluoroethylene were added at room temperature. Boron fluoride ether (173.07 mg, 1.22 mmol) and polymethylsiloxane (609.71 mg, 10.16 mmol) were heated to 90°C for 16 hours. Cool to room temperature, add 20 mL of water to dilute, and then extract with ethyl acetate (20 mL). Combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a residue. The residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:5) to obtain compound 3-6. LC-MS: m/z=559.3[M+H] + .
第七步Step 7
向化合物3-6(0.51g,912.82μmol)的甲醇(5mL)和四氢呋喃(5mL)溶液中加入氢氧化锂水溶液(4M,5mL)，在50℃下搅拌3小时。反应完全后，冷却至室温，加入醋酸调节pH至7左右，浓缩得到残留物。残留物用高效液相色谱法纯化(色谱柱:Phenomenex luna C18 250×50mm，10μm；流动相:A:水(0.225％甲 酸)；B:乙腈；方法B:25％-40％)分离纯化得到化合物3。LC-MS:m/z＝445.3[M+H]+。To a solution of compound 3-6 (0.51 g, 912.82 μmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was added aqueous lithium hydroxide solution (4 M, 5 mL), and the mixture was stirred at 50° C. for 3 hours. After the reaction is complete, cool to room temperature, add acetic acid to adjust the pH to about 7, and concentrate to obtain a residue. The residue was purified by high performance liquid chromatography (chromatographic column: Phenomenex luna C18 250×50mm, 10 μm; mobile phase: A: water (0.225% Acid); B: acetonitrile; Method B: 25%-40%) to isolate and purify compound 3. LC-MS: m/z=445.3[M+H] + .
第八步Step 8
化合物3用手性柱分离(色谱柱:Daicel ChiralPak IC 250×30mm.,10μm，流动相:A:二氧化碳，B:异丙醇(0.1％氨水)，方法：B:40％-40％)得到化合物3A和化合物3B。Compound 3 was obtained by chiral column separation (chromatographic column: Daicel ChiralPak IC 250×30mm., 10μm, mobile phase: A: carbon dioxide, B: isopropyl alcohol (0.1% ammonia), method: B: 40%-40%) Compound 3A and Compound 3B.
化合物3A表征：(保留时间:4.007min，ee＝100％，SFC分析方法：色谱柱:Chiralpak IC-3 50×4.6mm I.D.,3μm，流动相:A:二氧化碳，B:40％甲醇+60％乙腈(0.05％二乙胺)，梯度B％：0％-40％)，1H NMR(400MHz,DMSO-d6)δppm 10.81(s,1H),7.98-7.96(d,J＝8.0Hz,2H),7.76-7.74(d,J＝8.0Hz,2H),7.36-7.16(m,1H),6.71-6.63(m,1H),6.55-6.50(m,1H),3.80-3.74(m,4H),3.49-3.41(m,2H),3.23-3.14(m,3H),2.42(s,3H),2.19-1.94(m,2H),1.68-1.58(m,1H),1.55-1.46(m,1H),1.32-1.18(m,2H),0.68-0.50(m,1H),0.39-0.26(m,2H),0.15-0.05(m,2H)；LC-MS:m/z＝445.3[M+H]+。Characterization of compound 3A: (retention time: 4.007min, ee=100%, SFC analysis method: chromatographic column: Chiralpak IC-3 50×4.6mm ID, 3μm, mobile phase: A: carbon dioxide, B: 40% methanol + 60% Acetonitrile (0.05% diethylamine), gradient B%: 0%-40%), 1 H NMR (400MHz, DMSO-d 6 ) δppm 10.81 (s, 1H), 7.98-7.96 (d, J = 8.0Hz, 2H),7.76-7.74(d,J＝8.0Hz,2H),7.36-7.16(m,1H),6.71-6.63(m,1H),6.55-6.50(m,1H),3.80-3.74(m, 4H),3.49-3.41(m,2H),3.23-3.14(m,3H),2.42(s,3H),2.19-1.94(m,2H),1.68-1.58(m,1H),1.55-1.46( m,1H),1.32-1.18(m,2H),0.68-0.50(m,1H),0.39-0.26(m,2H),0.15-0.05(m,2H); LC-MS: m/z=445.3 [M+H] + .
化合物3B表征：(保留时间:4.505min，ee＝100％，SFC分析方法：色谱柱:Chiralpak IC-3 50×4.6mm I.D.,3μm，流动相:A:二氧化碳，B:40％甲醇+60％乙腈(0.05％二乙胺)，梯度B％：0％-40％)，1H NMR(400MHz,DMSO-d6)δppm 10.82(s,1H),8.01-7.88(d,J＝8.0Hz,2H),7.79-7.68(d,J＝8.0Hz,2H),7.31-7.21(m,1H),6.70-6.62(m,1H),6.59-6.52(m,1H),3.81-3.73(m,4H),3.49-3.41(m,2H),3.23-3.14(m,3H),2.43(s,3H),2.33-2.06(m,2H),1.89-1.76(m,2H),1.34-1.17(m,2H),0.99-0.90(m,1H),0.48-0.37(m,2H),0.04-0.06(m,2H)；LC-MS:m/z＝445.3[M+H]+。Characterization of compound 3B: (retention time: 4.505min, ee=100%, SFC analysis method: chromatographic column: Chiralpak IC-3 50×4.6mm ID, 3μm, mobile phase: A: carbon dioxide, B: 40% methanol + 60% Acetonitrile (0.05% diethylamine), gradient B%: 0%-40%), 1 H NMR (400MHz, DMSO-d 6 ) δppm 10.82 (s, 1H), 8.01-7.88 (d, J = 8.0Hz, 2H),7.79-7.68(d,J＝8.0Hz,2H),7.31-7.21(m,1H),6.70-6.62(m,1H),6.59-6.52(m,1H),3.81-3.73(m, 4H),3.49-3.41(m,2H),3.23-3.14(m,3H),2.43(s,3H),2.33-2.06(m,2H),1.89-1.76(m,2H),1.34-1.17( m,2H), 0.99-0.90(m,1H), 0.48-0.37(m,2H), 0.04-0.06(m,2H); LC-MS: m/z=445.3[M+H] + .
化合物3A相对3B在手性色谱柱中的保留时间短，化合物3B相对3A在手性色谱柱中的保留时间长。Compound 3A has a shorter retention time in the chiral chromatography column than 3B, and compound 3B has a longer retention time in the chiral chromatography column than 3A.
生物测试部分Biological testing section
实验例1：补体人Factor B蛋白结合测试(表面等离子体共振(surface plasmon resonance,SPR)法)Experimental Example 1: Complement human Factor B protein binding test (surface plasmon resonance (SPR) method)
实验目的：利用SPR方法，对待测化合物与人补体因子B之间结合的动力学常数和亲和力检测。Experimental purpose: Use SPR method to detect the kinetic constants and affinity of the binding between the test compound and human complement factor B.
实验方案：Experimental program:
将1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC)和N-羟基硫代琥珀酰亚胺钠盐(NHS)1:1混合，将补体因子B用PH 5.5的醋酸溶液稀释至20μg/ml，使用生物大分子相互作用分析仪Biacore 8K，按程序设置将EDC/NHS、FB蛋白溶液和1M的乙醇胺-盐酸溶液加入到检测板。将检测板放于机器检测仓，按程序依次将EDC/NHS混合液，补体因子B蛋白溶液和1M的乙醇胺-盐酸溶液注入CM5芯片表面，进行芯片的活化，配体偶联以及去活化。每个通道的流通池1作为参比通道仅进行表面活化和去活化，不注入补体因子B蛋白溶液。使用运行缓冲液(PBST)对所有样品储存液进行稀释，所有样品2复孔2倍连续梯度稀释6个点。将准备好的样品按程序设置转移到检测板中，将检测板置于Biacore 8K的样品仓。运行检测程序，样品按程序依次注入芯片各通道，结合时间120s，解离时间600s，流速30μL/min。使用Biacore Insight Evaluation Software对数据进行分析：使用1:1Binding Kinetics Model对数据进行拟合，得到各检测样品与补体因子B蛋白结合的结合速率常数(kon)，解离速率常数(koff)和解离平衡常数(KD)。Mix 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and N-hydroxysulfosuccinimide sodium salt (NHS) 1:1, and add complement Factor B was diluted to 20 μg/ml with PH 5.5 acetic acid solution, and the biological macromolecule interaction analyzer Biacore 8K was used to add EDC/NHS, FB protein solution and 1M ethanolamine-hydrochloric acid solution to the detection plate according to the program settings. Place the detection plate in the machine detection compartment, and inject the EDC/NHS mixture, complement factor B protein solution and 1M ethanolamine-hydrochloric acid solution into the surface of the CM5 chip according to the program to activate, ligand coupling and deactivate the chip. The flow cell 1 of each channel serves as the reference channel and only performs surface activation and deactivation without injecting complement factor B protein solution. All sample storage solutions were diluted with running buffer (PBST), and all samples were serially diluted 6 points in duplicate in 2-fold wells. Transfer the prepared samples to the detection plate according to the program settings, and place the detection plate in the sample compartment of Biacore 8K. Run the detection program, and the samples are injected into each channel of the chip sequentially according to the program. The binding time is 120s, the dissociation time is 600s, and the flow rate is 30 μL/min. Use Biacore Insight Evaluation Software to analyze the data: Use 1:1 Binding Kinetics Model to fit the data to obtain the binding rate constant (kon), dissociation rate constant (koff) and dissociation equilibrium of each test sample and the complement factor B protein. Constant (KD).
实验结果：Experimental results:
测试化合物对人补体Factor B蛋白的结合活性如表1所示。其中A代表：IC50值＜100nM；B代表：100nM≤IC50值≤1000nM；C代表：IC50值＞1000nM。The binding activity of the test compounds to human complement Factor B protein is shown in Table 1. Among them, A represents: IC 50 value <100nM; B represents: 100nM ≤ IC 50 value ≤ 1000nM; C represents: IC 50 value > 1000nM.
表1：本发明化合物体外人补体Factor B蛋白结合活性筛选试验结果
Table 1: In vitro human complement Factor B protein binding activity screening test results of the compounds of the present invention
结论：本发明化合物对人补体Factor B蛋白具有显著的结合活性。Conclusion: The compound of the present invention has significant binding activity to human complement Factor B protein.
实验例2：LPS诱导补体激活小鼠体内PD模型Experimental Example 2: LPS-induced complement activation in vivo mouse PD model
实验目的：考察本发明化合物对LPS刺激诱导小鼠补体激活的抑制作用。Experimental purpose: To investigate the inhibitory effect of the compound of the present invention on complement activation in mice induced by LPS stimulation.
实验动物：雌性C57BL/6J小鼠，7-9周龄，体重17-23克；供应商：上海西普尔-必凯实验动物有限公司。Experimental animals: female C57BL/6J mice, 7-9 weeks old, weighing 17-23 grams; supplier: Shanghai Sipur-Bika Experimental Animal Co., Ltd.
实验过程：experiment procedure:
在给药前4小时，将大肠杆菌(Sigma，L2880)中的100μg脂多糖(LPS)溶解在100μL无菌PBS(磷酸盐缓冲液pH 7.2-7.4)中通过腹腔内注射诱导小鼠补体激活。正常小鼠组(阴性对照)：动物接受腹膜内注射100μL无菌PBS，并通过灌饲法(IO)单独给药溶媒。模型组(阳性对照)：动物接受腹腔内LPS和PO给药溶媒(20％PEG400/10％solutol/70％水)。药物组：给药化合物(溶媒：20％PEG400/10％solutol/70％水，给药体积：5mL/kg，剂量：10mg/kg)后4小时，进行样品采集。Complement activation was induced in mice by intraperitoneal injection of 100 μg lipopolysaccharide (LPS) in Escherichia coli (Sigma, L2880) dissolved in 100 μL sterile PBS (phosphate buffer pH 7.2-7.4) 4 hours before administration. Normal mouse group (negative control): animals received an intraperitoneal injection of 100 μL of sterile PBS, and vehicle alone was administered by gavage (IO). Model group (positive control): animals received intraperitoneal LPS and PO administration of vehicle (20% PEG400/10% solutol/70% water). Drug group: Samples were collected 4 hours after compound administration (vehicle: 20% PEG400/10% solution/70% water, administration volume: 5 mL/kg, dose: 10 mg/kg).
样品采集：从眼眶静脉丛采集血液样本0.3mL。所有血样均加入规格为1.5mL的商品化EDTA-K2抗凝管中(供应商为江苏康健医疗用品有限公司)。血样采集后，在半小时内，于4℃、3000g离心10分钟吸取上清血浆，迅速至于干冰中，于-80℃冰箱保存，用于Western blot分析补体激活后下游C3d蛋白水平。Sample collection: 0.3 mL of blood sample was collected from the orbital venous plexus. All blood samples were added into commercial EDTA-K2 anticoagulant tubes with a specification of 1.5 mL (supplier is Jiangsu Kangjian Medical Products Co., Ltd.). After blood samples are collected, within half an hour, centrifuge at 4°C and 3000g for 10 minutes to aspirate the supernatant plasma, quickly transfer it to dry ice, and store it in a -80°C refrigerator for Western blot analysis of downstream C3d protein levels after complement activation.
样品分析：小鼠血浆(5μL)+Lysis buffer(裂解液，27.5μL)+Loading buffer(上样缓冲液，12.5μL)+Reducing buffer(还原缓冲液，5μL)混匀100℃孵育15min，上样量为5μL/孔，即每孔血浆上样量为0.5μL。实验结果：Sample analysis: Mouse plasma (5 μL) + Lysis buffer (lysis buffer, 27.5 μL) + Loading buffer (loading buffer, 12.5 μL) + Reducing buffer (reducing buffer, 5 μL), mix well, incubate at 100°C for 15 minutes, and load the sample The volume is 5 μL/well, that is, the plasma loading volume per well is 0.5 μL. Experimental results:
通过腹腔内注射诱导小鼠补体激活后，模型组小鼠血清中C3d蛋白水平与正常组相比升高60％～90％，在口服给药本发明化合物后，各药物组小鼠血清中C3d蛋白水平相对造模组下降了70％～90％，C3d蛋白水平下降显著，具体实验结果见附图1。After inducing complement activation in mice through intraperitoneal injection, the C3d protein level in the serum of mice in the model group increased by 60% to 90% compared with the normal group. After oral administration of the compound of the present invention, the C3d protein level in the serum of mice in each drug group increased by 60% to 90%. The protein level dropped by 70% to 90% compared to the modeling group, and the C3d protein level dropped significantly. The specific experimental results are shown in Figure 1.
实验结论：与正常组和模型造模组相比，本发明化合物能够显著抑制LPS刺激的补体激活。Experimental conclusion: Compared with the normal group and the model group, the compound of the present invention can significantly inhibit complement activation stimulated by LPS.
实验例3化合物的血浆蛋白结合率测试Test of plasma protein binding rate of compounds in Experimental Example 3
实验目的：采用平衡透析法评估本发明化合物在CD-1小鼠、SD大鼠、比格犬、食蟹猴和人血浆中的蛋白结合率。Experimental purpose: Use equilibrium dialysis method to evaluate the protein binding rate of the compound of the present invention in the plasma of CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys and humans.
试验方案：Test plan:
将受试化合物分别用透析缓冲液稀释到上述五个物种的血浆中，配制成终浓度为2μM的样品，然后将样品加入到96孔平衡透析装置中，在37℃下用磷酸盐缓冲溶液透析4小时。实验采用华法林(warfarin)作为对照化合物。血浆和缓冲液中受试化合物与warfarin的浓度用LC-MS/MS法进行测定。并通过以下公式计算化合物的游离率：PPB_Unbound(％)＝100*FC/TC，其中FC是透析板缓冲液端化合物的浓度；TC是透析板血浆端化合物的浓度；T0是零时刻血浆样品中化合物的浓度。实验结果见表2。 The test compound was diluted into the plasma of the above five species with dialysis buffer to prepare a sample with a final concentration of 2 μM. The sample was then added to a 96-well equilibrium dialysis device and dialyzed with phosphate buffer solution at 37°C. 4 hours. The experiment used warfarin as a control compound. The concentrations of test compounds and warfarin in plasma and buffer were determined by LC-MS/MS. And calculate the free rate of the compound through the following formula: PPB_Unbound (%) = 100* FC / TC , where F C is the concentration of the compound at the buffer end of the dialysis plate; T C is the concentration of the compound at the plasma end of the dialysis plate; T 0 is Concentration of compound in plasma sample at time zero. The experimental results are shown in Table 2.
表2本发明化合物血浆蛋白结合率结果
Table 2 Results of plasma protein binding rates of compounds of the present invention
结论：本发明化合物在各种属血浆中均具有中等的血浆蛋白结合率，预示在上述各种属的血浆中，本发明化合物的游离态药物浓度比例适中，具有良好的成药性质。Conclusion: The compound of the present invention has a moderate plasma protein binding rate in the plasma of various genera, which indicates that in the plasma of the above-mentioned various genera, the free drug concentration ratio of the compound of the present invention is moderate and has good pharmaceutical properties.
实验例4：化合物体外肝微粒体稳定性实验Experimental Example 4: In vitro liver microsome stability test of compounds
实验材料Experimental Materials
肝微粒体：购买于Corning或Xenotech，储存于-80℃冰箱；还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)，供应商：Chem-impex international，货号：00616；对照化合物：睾酮，双氯芬酸，普罗帕酮。Liver microsomes: purchased from Corning or Xenotech, stored in -80°C refrigerator; reduced nicotinamide adenine dinucleotide phosphate (NADPH), supplier: Chem-impex international, product number: 00616; control compounds: testosterone, diclofenac , propafenone.
实验步骤Experimental steps
(1)工作液的配制(1) Preparation of working fluid
储备液：10mM DMSO溶液；工作浓度配制：100％乙腈稀释到100μM(有机相含量：99％乙腈，1％DMSO)。Stock solution: 10mM DMSO solution; working concentration preparation: 100% acetonitrile diluted to 100μM (organic phase content: 99% acetonitrile, 1% DMSO).
(2)实验步骤(2)Experimental steps
准备2块96孔孵育板，分别命名为T60孵育板和NCF60孵育板。Prepare two 96-well incubation plates, named T60 incubation plate and NCF60 incubation plate respectively.
在T60孵育板和NCF60孵育板上分别加入445μL微粒体工作液(肝微粒体蛋白浓度为0.56mg/mL)，然后将上述孵育板放置于37℃水浴锅中预孵育大约10分钟。Add 445 μL of microsomal working solution (liver microsomal protein concentration is 0.56 mg/mL) to the T60 incubation plate and NCF60 incubation plate respectively, and then place the above-mentioned incubation plate in a 37°C water bath for pre-incubation for about 10 minutes.
预孵育结束后，在T60孵育板和NCF60孵育板上分别加入5μL供试品或对照化合物工作液，混匀。在NCF60孵育板上每孔添加50μL磷酸钾盐缓冲液启动反应；在T0终止板中加入180μL的终止液(含200ng/mL tolbutamide(甲苯磺丁尿)和200ng/mL labetalol(拉贝洛尔)的乙腈溶液)和6μL的NADPH再生体系工作液，从T60孵育板中取出54μL样品至T0终止板(T0样品产生)。在T60孵育板上每孔添加44μL NADPH再生体系工作液启动反应。在空白板中只添加54μL微粒体工作液、6μL的NADPH再生体系工作液和180μL的终止液。因此，在供试品或对照化合物的样品中，化合物、睾酮、双氯芬酸和普罗帕酮的反应终浓度为1μM，肝微粒体的浓度为0.5mg/mL，DMSO和乙腈在反应体系中的终浓度分别为0.01％(v/v)和0.99％(v/v)。After the pre-incubation, add 5 μL of test product or control compound working solution to the T60 incubation plate and NCF60 incubation plate respectively, and mix well. Add 50 μL potassium phosphate buffer to each well of the NCF60 incubation plate to start the reaction; add 180 μL stop solution (containing 200ng/mL tolbutamide (tolbutamide) and 200ng/mL labetalol (labetalol)) to the T0 stop plate. Acetonitrile solution) and 6 μL of NADPH regeneration system working solution, take 54 μL of sample from the T60 incubation plate to the T0 stop plate (TO sample generation). Add 44 μL NADPH regeneration system working solution to each well of the T60 incubation plate to start the reaction. Add only 54 μL of microsome working solution, 6 μL of NADPH regeneration system working solution and 180 μL of stop solution to the blank plate. Therefore, in the sample of the test product or control compound, the final concentration of the compound, testosterone, diclofenac and propafenone in the reaction is 1 μM, the concentration of liver microsomes is 0.5 mg/mL, and the final concentration of DMSO and acetonitrile in the reaction system 0.01% (v/v) and 0.99% (v/v) respectively.
孵育适当时间(如5、15、30、45和60分钟)后，分别在每个终止板的样品孔中加入180μL的终止液(含200ng/mL tolbutamide和200ng/mL labetalol的乙腈溶液)，之后从T60孵育板中取出60μL样品以终止反应。After incubating for an appropriate time (such as 5, 15, 30, 45 and 60 minutes), add 180 μL of stop solution (acetonitrile solution containing 200ng/mL tolbutamide and 200ng/mL labetalol) to the sample wells of each stop plate. Remove 60 μL of sample from the T60 incubation plate to stop the reaction.
所有样品板摇匀并在3220×g离心20分钟，然后每孔取80μL上清液稀释到240μL纯水中用于液相色谱串联质谱分析。实验结果见表3。All sample plates were shaken and centrifuged at 3220 × g for 20 minutes, and then 80 μL of the supernatant from each well was diluted into 240 μL of pure water for liquid chromatography-tandem mass spectrometry analysis. The experimental results are shown in Table 3.
表3：本发明化合物肝微粒体稳定性试验结果
Table 3: Liver microsome stability test results of the compounds of the present invention
结论：本发明化合物在人肝微粒体测试中表现出较好的代谢稳定性。Conclusion: The compounds of the present invention show good metabolic stability in human liver microsome tests.
实验例5：小鼠药代动力学评价 Experimental Example 5: Evaluation of Mouse Pharmacokinetics
受试化合物与5％DMSO/10％聚乙二醇-15羟基硬脂酸酯/85％水混合，涡旋并超声，制备得到0.2mg/mL澄清溶液，微孔滤膜过滤后备用。选取18至20克的Balb/c雄性小鼠，静脉注射给予候选化合物溶液，剂量1mg/kg；口服给予待测化合物溶液，剂量为10mg/kg。收集一定时间的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数(C0：静脉注射后瞬时的需要浓度；Cmax：给药后出现的血药浓度最高值；Tmax：给药后达到药峰浓度所需的时间；T1/2：血药浓度下降一半所需的时间；Vdss：表观分布容积，指药物在体内达到动态平衡时体内药量与血药浓度的比例常数。Cl：清除率，指单位时间从体内清除的药物表观分布容积数；AUC0-last：药时曲线下面积，指血药浓度曲线对时间轴所包围的面积；F：生物利用度)。The test compound was mixed with 5% DMSO/10% polyethylene glycol-15 hydroxystearate/85% water, vortexed and ultrasonicated to prepare a 0.2 mg/mL clear solution, which was filtered through a microporous membrane for later use. Select Balb/c male mice of 18 to 20 grams, and administer the candidate compound solution intravenously at a dose of 1 mg/kg; administer the test compound solution orally at a dose of 10 mg/kg. Collect whole blood for a certain period of time, prepare plasma, analyze drug concentration by LC-MS/MS method, and use Phoenix WinNonlin software (Pharsight Company, USA) to calculate pharmacokinetic parameters (C 0 : instantaneous required concentration after intravenous injection; C max : The highest value of blood drug concentration after administration; T max : the time required to reach the peak drug concentration after administration; T 1/2 : the time required for the blood drug concentration to drop by half; V dss : apparent volume of distribution, refers to The proportional constant between the amount of drug in the body and the blood drug concentration when the drug reaches dynamic equilibrium in the body. Cl: clearance rate, which refers to the apparent distribution volume of the drug cleared from the body per unit time; AUC 0-last : the area under the drug time curve, which refers to the blood concentration The area enclosed by the drug concentration curve versus the time axis; F: bioavailability).
本发明化合物展现了较长的半衰期和较高的药物暴露量，具有良好的体内药物代谢动力学性质。The compound of the present invention exhibits a longer half-life and higher drug exposure, and has good pharmacokinetic properties in vivo.
实验例6：大鼠药代动力学研究试验Experimental Example 6: Rat pharmacokinetics research test
选取雄性SD大鼠(6-8周龄，体重200-300克)。Male SD rats (6-8 weeks old, weighing 200-300 grams) were selected.
注射给药(IV)，剂量为1mpk，浓度为0.20mg/mL，溶媒为20％PEG400/10％solutol/70％水；口服给药(PO)，剂量为10mpk，浓度为1mg/mL，溶媒为20％PEG400/10％solutol/70％水。For injection (IV), the dose is 1mpk, the concentration is 0.20mg/mL, the solvent is 20% PEG400/10% solution/70% water; for oral administration (PO), the dose is 10mpk, the concentration is 1mg/mL, the solvent It is 20%PEG400/10%solutol/70%water.
样品采集：实验动物每个时间点从隐静脉穿刺采集血液样本0.03mL，记录实际采血时间。所有血样均加入规格为1.5mL的商品化EDTA-K2抗凝管中。血样采集后，血浆基质当中添加DDV做稳定剂，其中，血浆：敌敌畏溶液＝40:1，敌敌畏溶液为40mM敌敌畏的乙腈/水(1:1)溶液，在半小时内，于4℃、3000g离心10分钟吸取上清血浆，迅速置于干冰中，于-80℃冰箱保存，用于LC-MS/MS分析。Sample collection: 0.03 mL of blood sample was collected from the saphenous vein puncture of the experimental animals at each time point, and the actual blood collection time was recorded. All blood samples were added into commercial EDTA-K2 anticoagulant tubes with a specification of 1.5 mL. After the blood sample is collected, DDV is added to the plasma matrix as a stabilizer. Plasma: dichlorvos solution = 40:1. The dichlorvos solution is a 40mM dichlorvos acetonitrile/water (1:1) solution. Within half an hour, the solution is heated at 4°C and 3000g. Centrifuge for 10 minutes to aspirate the supernatant plasma, quickly place it in dry ice, and store it in a -80°C refrigerator for LC-MS/MS analysis.
采用Phoenix WinNonlin 6.3药动学软件的非房室模型处理血浆浓度，使用线性对数梯形法方法计算药动学参数。C0：静脉注射后瞬时的需要浓度；Cmax：给药后出现的血药浓度最高值；Tmax：给药后达到药峰浓度所需的时间；T1/2：血药浓度下降一半所需的时间；Vdss：表观分布容积，指药物在体内达到动态平衡时体内药量与血药浓度的比例常数。Cl：清除率，指单位时间从体内清除的药物表观分布容积数；AUC0- last：药时曲线下面积，指血药浓度曲线对时间轴所包围的面积；F：生物利用度。实验结果见表4。The non-compartmental model of Phoenix WinNonlin 6.3 pharmacokinetic software was used to process plasma concentration, and the linear logarithmic trapezoidal method was used to calculate pharmacokinetic parameters. C 0 : the instantaneous required concentration after intravenous injection; C max : the highest blood drug concentration after administration; T max : the time required to reach the peak drug concentration after administration; T 1/2 : the blood drug concentration drops by half The time required; V dss : apparent volume of distribution, which refers to the proportional constant between the amount of drug in the body and the concentration of the drug in the blood when the drug reaches dynamic equilibrium in the body. Cl: clearance rate, which refers to the apparent distribution volume of the drug cleared from the body per unit time; AUC 0- last : area under the drug-time curve, which refers to the area surrounded by the blood drug concentration curve against the time axis; F: bioavailability. The experimental results are shown in Table 4.
表4本发明化合物的大鼠PK结果
Table 4 Rat PK results of compounds of the present invention
“--”是指未测试或未获得数据。"--" means no testing or no data obtained.
实验结论：本发明化合物展现了较长的半衰期和较高的口服血浆暴露量，具有良好的药代动力学性质。Experimental conclusion: The compound of the present invention exhibits a longer half-life and higher oral plasma exposure, and has good pharmacokinetic properties.
实验例7：体外Caco-2细胞渗透性测试Experimental Example 7: In vitro Caco-2 cell permeability test
细胞培养：Cell culture:
细胞培养使用添加了2mM的L-谷氨酰胺，10％胎牛血清(FBS)，100U/mL青霉素-G以及100μg/mL链霉素的MEM(最低必需培养基)。细胞培养条件为37±1℃，5％CO2及饱和湿度。待细胞长至80-90％密集度，加入胰酶(0.05％,w/v)/EDTA(0.02％,w/v)消化液消化细胞后种板。细胞接种于BD Falcon的Transwell-96孔板里，接种密度为1×105细胞/cm2。细胞置于二氧化碳培养箱中培养22天后用于转运实验。 Cell culture uses MEM (minimum essential medium) supplemented with 2mM L-glutamine, 10% fetal bovine serum (FBS), 100U/mL penicillin-G, and 100μg/mL streptomycin. Cell culture conditions are 37±1°C, 5% CO2 and saturated humidity. When the cells grow to 80-90% density, add trypsin (0.05%, w/v)/EDTA (0.02%, w/v) digestion solution to digest the cells and then seed the plate. Cells were seeded in BD Falcon Transwell-96 well plates at a seeding density of 1×10 5 cells/cm 2 . The cells were cultured in a carbon dioxide incubator for 22 days and then used for transport experiments.
转运实验：Transport experiment:
本项目采用含10mM HEPES的Hank’s平衡盐缓冲液(pH 7.40±0.05)为转运缓冲液。测试受试化合物和阳性药地高辛在2μM浓度下的双向转运，各两个平行样本，测试非诺特罗和普萘洛尔从顶端到基底端(A-B)的转运。孵育体系中DMSO的浓度控制在1％以下，加样后，将细胞板置于37±1℃，5％CO2及饱和湿度条件下孵育120分钟，所有的样品漩涡震荡后于3220rpm，20℃离心20分钟，对照品和供试品用超纯水1：1(v：v)稀释后储存于4℃，采用液相色谱串联质谱(LC/MS/MS)进行分析测试。This project uses Hank's balanced salt buffer (pH 7.40±0.05) containing 10mM HEPES as the transport buffer. The test compound and the positive drug digoxin were tested for bidirectional transport at a concentration of 2 μM, with two parallel samples each, and the apical to basal (AB) transport of fenoterol and propranolol. The concentration of DMSO in the incubation system is controlled below 1%. After adding the sample, place the cell plate and incubate it for 120 minutes at 37±1℃, 5% CO2 and saturated humidity. All samples are vortexed and shaken at 3220rpm and 20℃. Centrifuge for 20 minutes, dilute the control substance and test substance with ultrapure water 1:1 (v:v) and store at 4°C. Analyze and test using liquid chromatography tandem mass spectrometry (LC/MS/MS).
样品分析：Sample analysis:
本研究采用液相色谱串联质谱(LC/MS/MS)方法半定量分析起始溶液、接收液和给药孔上清液中受试化合物和对照品非诺特罗、普萘诺尔以及地高辛与内标的峰面积比值。采用如下公式计算表观渗透系数(Papp,cm/s)，外排率以及回收率：In this study, the liquid chromatography tandem mass spectrometry (LC/MS/MS) method was used to semi-quantitatively analyze the test compounds and reference substances fenoterol, propranolol and digoxin in the starting solution, receiving solution and administration well supernatant. The peak area ratio of the internal standard. Use the following formula to calculate the apparent permeability coefficient (P app ,cm/s), efflux rate and recovery rate:
(1)Papp＝(dCr/dt)×Vr/(A×C0)，dCr/dt是化合物在单位时间内接收端的累积浓度(μM/s)；Vr是接收端溶液的体积(顶端和基底端的溶液体积分别为0.075mL和0.250mL)；A是胞单层的相对表面积(0.0804cm2)；C0是给药端供试品的起始浓度(nM)或对照品的峰面积比值。
(2)外排比＝Papp(BA)/Papp(AB)(1)P app = (dC r /d t )×V r /(A×C 0 ), dC r /d t is the cumulative concentration of the compound at the receiving end per unit time (μM/s); V r is the receiving end The volume of the solution (the solution volumes at the top and basal ends are 0.075mL and 0.250mL respectively); A is the relative surface area of the cell monolayer (0.0804cm 2 ); C 0 is the initial concentration of the test substance at the administration end (nM) or Peak area ratio of reference substance.
(2) External displacement ratio=P app (BA)/P app (AB)
(3)回收率(％)＝100×[(Vr×Cr)+(Vd×Cd)]/(Vd×C0)，C0是给药端供试品的起始浓度(nM)或对照品的峰面积比值；Vd是给药端的体积(顶侧为0.075mL，基底侧为0.250mL)；Cd和Cr分别为给药端和接收端供试品的终浓度(nM)或对照品的峰面积比值。 ( 3 ) Recovery rate (%) = 100× [ ( V r (nM) or the peak area ratio of the reference substance; V d is the volume of the dosing end (0.075mL on the top side and 0.250mL on the basal side); C d and C r are the terminal volumes of the test sample at the dosing end and receiving end respectively. Concentration (nM) or peak area ratio of reference substance.
实验结果见表5。The experimental results are shown in Table 5.
表5.Caco-2细胞渗透性测试结果
Table 5. Caco-2 cell permeability test results
结论：本发明化合物具有较好的渗透性。 Conclusion: The compound of the present invention has good permeability.

Claims (15)

  1. 式(I)所示化合物或其药学上可接受的盐，
    The compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
    其中，in,
    R1选自H、D、F、Cl、Br、I、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Ra取代；R 1 is selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R a ;
    R2选自H、D、F、Cl、Br、I、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rb取代；R 2 is selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R b ;
    R3选自H、D、F、Cl、Br、I、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rc取代；R 3 is selected from H, D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1- 3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R c ;
    R4选自C1-6烷硫基、C2-6烯基、C2-6炔基、C3-6环烷基和3-6元杂环基，所述C1-6烷硫基、C2-6烯基、C2-6炔基、C3-6环烷基和3-6元杂环基分别独立地任选被1、2、3或4个Rd取代；R 4 is selected from C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, the C 1-6 alkylthio base, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are independently optionally substituted by 1, 2, 3 or 4 R d ;
    各R5分别独立地选自D、F、Cl、Br、I、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Re取代；Each R 5 is independently selected from D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy groups are independently optionally substituted by 1, 2 or 3 Re ;
    各Ra分别独立地选自D、F、Cl、Br和I；Each R a is independently selected from D, F, Cl, Br and I;
    各Rb分别独立地选自D、F、Cl、Br和I；Each R b is independently selected from D, F, Cl, Br and I;
    各Rc分别独立地选自D、F、Cl、Br和I；Each R c is independently selected from D, F, Cl, Br and I;
    各Rd分别独立地选自D、F、Cl、Br、I、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个R取代；Each R d is independently selected from D, F, Cl, Br, I, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R;
    各Re分别独立地选自D、F、Cl、Br和I；Each Re is independently selected from D, F, Cl, Br and I;
    各R分别独立地选自D、F、Cl、Br和I；Each R is independently selected from D, F, Cl, Br and I;
    m选自0、1、2和3。m is selected from 0, 1, 2 and 3.
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，各Rd分别独立地选自D、F、Cl、CN、OH、NH2、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个R取代；或者，各Rd分别独立地选自F和C1-3烷基，所述C1-3烷基任选被1、2或3个R取代；或者，各Rd分别独立地选自F和甲基。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R d is independently selected from D, F, Cl, CN, OH, NH 2 , C 1-3 alkyl and C 1-3 Alkoxy group, the C 1-3 alkyl group and C 1-3 alkoxy group are each independently optionally substituted by 1, 2 or 3 R; alternatively, each R d is independently selected from F and C 1- 3 alkyl, the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R; alternatively, each R d is independently selected from F and methyl.
  3. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R1选自C1-3烷基，所述C1-3烷基任选被1、2或3个Ra取代；或者，R1选自CH3，所述CH3任选被1、2或3个Ra取代；或者R1选自CH3和CD3。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ; Alternatively, R1 is selected from CH3 , optionally substituted with 1, 2 or 3 Ra ; or R1 is selected from CH3 and CD3 .
  4. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R2选自C1-3烷氧基，所述C1-3烷氧基任选被1、2或3个Rb取代；或者，R2选自OCH3，所述OCH3任选被1、2或3个Rb取代；或者，R2选自OCH3和OCD3。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 1-3 alkoxy, and the C 1-3 alkoxy is optionally replaced by 1, 2 or 3 R b Substituted; alternatively, R 2 is selected from OCH 3 , which is optionally substituted by 1, 2 or 3 R b ; alternatively , R 2 is selected from OCH 3 and OCD 3 .
  5. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R3选自H、F和C1-3烷基，所述C1-3烷基任选被1、2或3个Rc取代；或者，R3选自H、F和CH3；或者，R3选自H。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, F and C 1-3 alkyl, and the C 1-3 alkyl is optionally replaced by 1, 2 or 3 R c is substituted; alternatively, R 3 is selected from H, F and CH 3 ; alternatively, R 3 is selected from H.
  6. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R4选自C1-6烷硫基、C2-6烯基、C2-6炔基和C3-6环烷基，所述C1-6烷硫基、C2-6烯基、C2-6炔基和C3-6环烷基分别独立地任选被1、2、3或4个Rd取代；或者，R4选自C1-3烷硫基、C2-3烯基、C2-3炔基和C3-4环烷基，所述C1-3烷硫基、C2-3烯基、C2-3炔基和C3-4环烷基分别独立地任选被1、2、3或4个Rd取代。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl base, the C 1-6 alkylthio group, C 2-6 alkenyl group, C 2-6 alkynyl group and C 3-6 cycloalkyl group are each independently optionally substituted by 1, 2, 3 or 4 R d ; Alternatively, R 4 is selected from C 1-3 alkylthio, C 2-3 alkenyl, C 2-3 alkynyl and C 3-4 cycloalkyl, the C 1-3 alkylthio, C 2- 3 alkenyl, C 2-3 alkynyl and C 3-4 cycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R d .
  7. 根据权利要求6所述化合物或其药学上可接受的盐，其中，R4选自 所述分别独立地任选被1、2、3或4个Rd取代；或者，R4选自所述分别独立地任选被1、2、3或4个Rd取代；或者，R4选自 或者，R4选自 The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from described Each independently optionally substituted by 1, 2, 3 or 4 R d ; alternatively, R 4 is selected from described Each independently optionally substituted by 1, 2, 3 or 4 R d ; alternatively, R 4 is selected from Alternatively, R 4 is selected from
  8. 根据权利要求1所述化合物或其药学上可接受的盐，其中，m选自0。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein m is selected from 0.
  9. 根据权利要求1所述化合物或其药学上可接受的盐，上述各Ra、各Rb、各Rc、各Re和各R分别独立地选自D和F。According to the compound of claim 1 or a pharmaceutically acceptable salt thereof, each of the above-mentioned R a , each R b , each R c , each Re and each R are independently selected from D and F.
  10. 根据权利要求1～9任意一项所述化合物或其药学上可接受的盐，其选自式(P)化合物、式(P-1)化合物或式(P-2)化合物，
    The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of compounds of formula (P), compounds of formula (P-1) or compounds of formula (P-2),
    其中，R1、R2、R3和R4如权利要求1～9任意一项所定义。Among them, R 1 , R 2 , R 3 and R 4 are as defined in any one of claims 1 to 9.
  11. 根据权利要求10所述化合物或其药学上可接受的盐，其中， The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein,
    R1选自C1-3烷基，所述C1-3烷基任选被1、2或3个Ra取代；R 1 is selected from C 1-3 alkyl, which is optionally substituted by 1, 2 or 3 R a ;
    R2选自C1-3烷氧基，所述C1-3烷氧基任选被1、2或3个Rb取代；R 2 is selected from C 1-3 alkoxy, which is optionally substituted by 1, 2 or 3 R b ;
    R3选自H；R 3 is selected from H;
    R4选自C1-3烷硫基、C2-3烯基、C2-3炔基和C3-4环烷基，所述C1-3烷硫基、C2-3烯基、C2-3炔基和C3-4环烷基分别独立地任选被1、2、3或4个Rd取代；R 4 is selected from C 1-3 alkylthio, C 2-3 alkenyl, C 2-3 alkynyl and C 3-4 cycloalkyl, the C 1-3 alkylthio, C 2-3 alkenyl , C 2-3 alkynyl and C 3-4 cycloalkyl are independently optionally substituted by 1, 2, 3 or 4 R d ;
    各Ra分别独立地选自D、F、Cl、Br和I；Each R a is independently selected from D, F, Cl, Br and I;
    各Rb分别独立地选自D、F、Cl、Br和I；Each R b is independently selected from D, F, Cl, Br and I;
    各Rd分别独立地选自D、F、Cl、Br、I、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个R取代；Each R d is independently selected from D, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are respectively independently optionally substituted by 1, 2 or 3 R;
    各R分别独立地选自D、F、Cl、Br和I。Each R is independently selected from D, F, Cl, Br and I.
  12. 下列所示化合物或其药学上可接受的盐，

    The following compounds or pharmaceutically acceptable salts thereof,

  13. 根据权利要求12所述化合物或其药学上可接受的盐，其化合物选自，



    The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from,



  14. 药物组合物，其含有治疗有效量的权利要求1～13任意一项所述化合物或其药学上可接受的盐，可选地，还包括药学上可接受的载体。A pharmaceutical composition containing a therapeutically effective amount of the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and optionally, a pharmaceutically acceptable carrier.
  15. 权利要求1～13任意一项所述化合物或其药学上可接受的盐或权利要求14所述的药物组合物在制备治疗与补体因子B相关疾病的药物中的应用。 Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 14 in the preparation of a medicament for treating diseases related to complement factor B.
PCT/CN2023/115288 2022-08-29 2023-08-28 Series of nitrogen-containing bridged heterocyclic compounds and preparation method therefor WO2024046277A1 (en)

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CN105579444A (en) * 2013-07-15 2016-05-11 诺华股份有限公司 Piperidinyl indole derivatives and their use as complement factor b inhibitors
CN114057758A (en) * 2020-08-07 2022-02-18 上海美悦生物科技发展有限公司 Complement factor B inhibitor and pharmaceutical composition, preparation method and application thereof
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CN116438170A (en) * 2020-12-30 2023-07-14 江苏恒瑞医药股份有限公司 Nitrogen-containing bridge heterocyclic compound, preparation method thereof and application thereof in medicine

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CN105579444A (en) * 2013-07-15 2016-05-11 诺华股份有限公司 Piperidinyl indole derivatives and their use as complement factor b inhibitors
CN114057758A (en) * 2020-08-07 2022-02-18 上海美悦生物科技发展有限公司 Complement factor B inhibitor and pharmaceutical composition, preparation method and application thereof
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